Burnet's Clonal Selection Theory Research Articles

Comparison of Burnet's clonal selection theory with tumor cell-clone development.

Increasing evidence has shown that Darwin's theory of evolution provides vital insights into the emergence and etiology of different types of cancer. On a microscopic scale, cancer stem cells meet the conditions for the Darwinian process of natural selection. In particular, cancer stem cells undergo cell reproduction characterized by the emergence of heritable variability that promotes replication and cell survival.Methods: Evidence from previous studies was gathered to compare Burnet's clonal selection theory with the tumor evolution theory.Results: The findings show that the Darwinian theory offers a general framework for understanding fundamental aspects of cancer. As fundamental theoretical frameworks, Burnet's clonal selection theory and the tumor evolution theory can be used to explain cancer cell evolution and identify the beneficial adaptations that contribute to cell survival in tissue landscapes and tissue ecosystems.Conclusions: In conclusion, this study shows that both Burnet's clonal selection theory and the tumor evolution theory postulate that cancer cells in tissue ecosystems evolve through reiterative processes, such as clonal expansion, clonal selection, and genetic diversification. Therefore, both theories provide insights into the complexities and dynamics of cancer, including its development and progression. Finally, we take into account the occurrence of biologic variation in both tumor cells and lymphocytes. It is important to note that the presence of lymphocyte variations appears to be advantageous in the framework of tumor defense but also dangerous within the framework of autoimmune disease development.

Reverse Transcriptase Mechanism of Somatic Hypermutation: 60 Years of Clonal Selection Theory.

The evidence for the reverse transcriptase mechanism of somatic hypermutation is substantial and multifactorial. In this 60th anniversary year of the publication of Sir MacFarlane Burnet’s Clonal Selection Theory, the evidence is briefly reviewed and updated.

The Evolutionary Origin of the Immune System, Neonatal Tolerance, Mhc Restriction

Immunology has made tremendous progress during more than half century after Burnet's clonal selection theory was published, but there are still more questions than answers. What is the function of the immune system, given that invertebrates have lived without one for millions of years, although they are also susceptible to infections and tumors? On the other hand, the emergence of the immune system in evolution did not deliver higher animals from either infections or cancer. The concept of linked functions is an attempt at answering these and other related questions. The concept assumes that the evolutionary origin of the immune system is related to a primary nonimmune function rather than to self/ nonself recognition. However, the mechanisms used to fulfill this function proved to be a suitable basis for immune recognition, which, according to the concept, occurs at the level of receptor-bearing immune cells rather than receptors themselves. Since cross-reactivity is a common phenomenon, it is assumed that specific combinations of antigenic determinants, rather than determinants per se, serve as recognition criteria, antigen processing and MCH-II restriction being necessary steps of the immune recognition of these combinations. The new views on adaptive immunity suggest new approaches to preventing graft rejection and treating chronic infections and malignant tumors.

Gordon Leslie Ada 1922–2012

GordonAda, an outstanding virologist and immunologist,was the first to demonstrate that the influenza virus genome is composed of RNA, not DNA. In immunology he provided evidence that refuted the template theory of antibody formation and performed elegant experiments to prove Burnet's Clonal Selection Theory. His administrative skills created a research environment that nurtured the Doherty-Zinkernagel Nobel Prize in viral immunology and allowed him to assist WHO and others greatly in developing effective vaccines.

Autoimmune hepatitis: What must be said

Autoimmune hepatitis (AIH) was first studied under its earlier name of “chronic active hepatitis” (CAH) from the 1950s, coincident with a renaissance of interest in autoimmunity. The definition of autoimmune serum reactants in disease, including CAH, gave new insights into chronic hepatitis and liver cirrhosis, and led to refinements of Burnet's clonal selection theory of acquired immunity, 1957–59. Various discoveries including serological reactants in CAH prompted its designation in 1965 as autoimmune hepatitis, and treatment with immunosuppressive drug regimens transformed outcomes and survival. Serological observations further indicated that AIH could exist as either of two types, clinically similar but genetically different: Type 1 aligned more with the non-organ-specific multisystem diseases, and the infrequent Type 2 more with the organ-specific diseases. However, events in either type that could explain the onset of autoimmunity in the normally tolerogenic milieu of the liver have not been discerned. In the genetically predisposed individual, initiation may depend on non-specific death of hepatocytes after which fragments derived from disordered apoptosis acquire the capacity for ongoing auto-immunogenic stimulation. Insufficiency in numbers and function of Treg populations appears important in the promotion of this autoimmune process.

Regulatory T‐cell differentiation versus clonal deletion of autoreactive thymocytes

The concept of clonal deletion of immune cells that carry an autoreactive antigen receptor was a central prediction of Burnet's clonal selection theory. A series of classical experiments in the late 1980s revealed that certain immature thymocytes upon encounter of 'self' are indeed removed from the T-cell repertoire before their release into the blood circulation. A second essential cornerstone of immunological tolerance, not anticipated by Burnett, has more recently surfaced through the discovery of Foxp3(+) regulatory T cells (Treg). Intriguingly, it appears that the expression of an autoreactive T-cell receptor is a shared characteristic of T cells that are subject to clonal deletion as well as of those deviated into the Treg lineage. This is all the more striking as Treg differentiation for the most part branches off from mainstream CD4T cell development during thymocyte maturation in the thymus, that is, it may neither temporally nor spatially be separated from clonal deletion. This raises the question of how an apparently identical stimulus, namely the encounter of 'self' during thymocyte development, can elicit fundamentally different outcomes such as apoptotic cell death on the one hand or differentiation into a highly specialized T-cell lineage on the other hand. Here, we will review the T-cell intrinsic and extrinsic factors that have been implicated in intrathymic Treg differentiation and discuss how these parameters may determine whether an autoreactive major histocompatibility complex class II-restricted thymocyte is deviated into the Treg lineage or subject to clonal deletion.

The enunciation and impact of Macfarlane Burnet's clonal selection theory of acquired immunity

The enunciation and impact of Macfarlane Burnet's clonal selection theory of acquired immunity

The golden anniversary of Burnet's clonal selection theory

The golden anniversary of Burnet's clonal selection theory

The clonal selection theory: 50 years since the revolution

October 2007 marks the 50th anniversary of the publication of Frank Macfarlane Burnet's clonal selection theory in the Australian Journal of Science. This short article, republished at the end of this commentary, revolutionized the field of immunology.

One cell–one antibody: prelude and aftermath

This year marks the 50th anniversary of Burnet's clonal selection theory. Here Gustav Nossal recounts his pioneering work that supported Burnet's theory and led to the death of the direct template hypothesis.

Darwinism and immunology: from Metchnikoff to Burnet.

Historical Insight: During those periods when immunology was oriented toward medical or biological subjects, Darwinian concepts predominated. These included Metchnikoff's phagocytic theory and Ehrlich's receptor theory during the early years and Burnet's clonal selection theory after the 1950s. During the immunochemically oriented interim, instruction theories were not so much anti- as a-Darwinian.

Targeted disruption of mu chain membrane exon causes loss of heavy-chain allelic exclusion.

Burnet's clonal selection theory suggests that each B lymphocyte is committed to a single antibody specificity. This is achieved by a programme of somatic rearrangements of the gene segments encoding antibody variable (V) regions, in the course of B-cell development. Evidence from immunoglobulin-transgenic mice and immunoglobulin-gene-transfected transformed pre-B cells suggest that the membrane form of the immunoglobulin heavy (H) chain of class mu (microns), expressed from a rearranged H-chain (IgH) locus, may signal allelic exclusion of the homologous IgH locus in the cell and initiation of light (L)-chain gene rearrangement in the Ig kappa loci. We report here that targeted disruption of the membrane exon of the mu chain indeed results in the loss of H-chain allelic exclusion. But, some kappa chain gene rearrangement is still observed in the absence of micron expression.

Mathematical model of antiviral immune response. I. Data analysis, generalized picture construction and parameters evaluation for hepatitis B

The present approach to the mathematical modelling of infectious diseases is based upon the idea that specific immune mechanisms play a leading role in development, course, and outcome of infectious disease. The model describing the reaction of the immune system to infectious agent invasion is constructed on the bases of Burnet's clonal selection theory and the co-recognition principle. The mathematical model of antiviral immune response is formulated by a system of ten non-linear delay-differential equations. The delayed argument terms in the right-hand part are used for the description of lymphocyte division, multiplication and differentiation processes into effector cells. The analysis of clinical and experimental data allows one to construct the generalized picture of the acute form of viral hepatitis B. The concept of the generalized picture includes a quantitative description of dynamics of the principal immunological, virological and clinical characteristics of the disease. Data of immunological experiments in vitro and experiments on animals are used to obtain estimates of permissible values of model parameters. This analysis forms the bases for the solution of the parameter identification problem for the mathematical model of antiviral immune response which will be the topic of the following paper (Marchuk et al., 1991, J. theor. Biol. 15).

Present status of tumor immunology in clinical gynecology.

The function of the immune system is to protect the body from damage caused by invading microorganisms, that is, bacteria, viruses, fungi, and parasites. The humoral mechanism functions through plasma cells producing antibodies that control bacterial infections. Viruses, fungi and parasites are controlled through the thymus dependent T lymphocytes. It is now clear that cancers also invoke immunologic reactions in their hosts. Cancer cells, like bacteria and viruses have their own characteristic antigens. An antigen is defined as a substance, usually a protein or polysaccharide, that the body recognizes as foreign, and to whose presence it reacts by forming antibodies. Antigenic differences represent the first known qualitative distinction between cancer cells and their normal counterparts. These qualitative differences between normal and cancer cells had escaped other methods of investigation, but were revealed by immunological techniques that take advantage of the extraordinary power of discrimination of the immune defense mechanism itself. This mechanism is capable of distinguishing even minute differences between protein molecules, probably one different amino acid in a chain of several thousand. Burnet's clonal selection theory has become the central dogma of immunology. It can be summarized by saying that lymphocytes have been destined from time immemorial to identify a specific antigen. When the lymphocyte encounters that antigen it becomes a sensitized lymphocyte, and on contact with similar antigens again produces an immune response including the production of very potent pharmacologic agents called lymphokines. Immunodeficiency diseases are identified by increased frequency of infections in patients. The impaired immunity decreases the patient's protection against developing a malignancy. Autoimmunity is the reaction of the immune system against the body's own tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Editors' corner

A tenet of F. Macfarlane Burnet's clonal selection theory is that a potential antibody-forming cell is genetically preprogrammed to synthesize antibodies of a single specificity. Gus Nossal, one of Burnet's colleagues, proposed that the theory could be disproved if a single cell produced antibodies of different specificities. Nossal, along with Joshua Lederberg, designed an experiment using a technique allowing them to detect the specificity of antibodies produced by individual antibody-producing cells. This microdrop technique, used with several different antigens, consistently demonstrated that virtually all cells tested produced antibodies of a single specificity; this led to the concept of one cell:one antibody. Support for this conclusion came from other studies, including immunofluorescent observations of antibody-forming cells and identification of the cell surface receptors on B lymphocytes. In the clinic, patients with multiple myeloma, a disease characterized by the appearance in serum of a large amount of homogeneous immunoglobulin, possess malignantly transformed cells, all of which arise from a single precursor and synthesize a single immunoglobulin molecule. Production of antibody of a single specificity by plasma cells allowed development of monoclonal antibodies that have greatly enhanced the therapeutic and laboratory choices available to investigators.