The birth of immunology. II. Metchnikoff and his critics

The presentation of the phagocytic theory of immunity, proposed by Metchnikoff in 1883, was immediately attacked by German pathologists and microbiologists. Led by Baumgarten and Ziegler, criticism was levied against the hypothesis in three general respects: 1) Can an analogy truly be established between leukocyte phagocytosis and feeding of monocellular organisms? 2) What is compelling about the phagocytic process as a universal defensive activity? 3) General philosophic objections were raised, centered upon the accusation of a teleologic formulation. Underlying the argument was the rejection of the notion that the response of phagocytic leukocytes was truly causal in the successful response to infection. We note that the humoral school of immunity was not established until 1888-1890, and the early debate between Metchnikoff and his detractors was not over an alternative theory of an active immune response. There was none. With the development of the humoralist position, in direct response to Metchnikoff's formulation, a true dialogue about immunity, in the modern context of active host response, was initiated. The debate at this point changed to issues of mechanism (cellular versus humoral effectors), and the relative importance of defining innate versus acquired immune processes. Our study traces the scientific and logical basis of the initial rejection of the phagocytosis theory. More broadly, the analysis of this debate elucidates the emergence of a new concept of immunity that rested upon the notion of an active host response. The humoralists erected their theory on Metchnikoff's original scaffold, and the ensuing debate of the nascent science relied on the successful establishment of his basic concept. With the studies of Bordet, Metchnikoff's protégé, the essential resolution of the acrimonious debate was offered. Metchnikoff continued his research by attempting to apply the phagocytosis theory to mechanisms of senility, while immunology oriented itself toward the biochemical definition of immune recognition.     

Human nicotinic acetylcholine receptor alpha-subunit isoforms: origins and expression.

A majority of the autoantibodies in the disease myasthenia gravis (MG) are directed against the alpha-subunit of the muscle nicotinic acetylcholine receptor (AChR). Unlike AChR alpha-subunits previously characterised from other species, the human alpha-subunit exists as two isoforms. The isoforms are generated by alternate splicing of an additional exon located between exons P3 and P4, termed P3A. The 25 amino acids encoded by the P3A exon are incorporated into the extracellular region of the alpha-subunit, and so may be relevant to the pathogenesis of MG. Genomic sequences from rhesus monkey, and from dog and cat, which are susceptible to MG, were characterised between AChR alpha-subunit exons P3 and P4. Although regions homologous to the P3A exon were identified for each of these species, analysis by RT-PCR showed that they are not expressed. At variance with a previous report, constitutive expression of mRNA encoding the human P3A+ alpha-subunit isoform was not detected in heart, kidney, liver, lung or brain. Differential expression of the two alpha-subunit isoforms was not seen during fetal muscle development or in muscle from MG patients. In all cases where mRNAs encoding the two alpha-subunit isoforms have been detected, they are present at an approximate 1:1 ratio.     

The bacteriophage, its role in immunology: how Macfarlane Burnet's phage research shaped his scientific style

The Australian scientist Frank Macfarlane Burnet-winner of the Nobel Prize in 1960 for his contributions to the understanding of immunological tolerance-is perhaps best recognized as one of the formulators of the clonal selection theory of antibody production, widely regarded as the 'central dogma' of modern immunology. His work in studies in animal virology, particularly the influenza virus, and rickettsial diseases is also well known. Somewhat less known and publicized is Burnet's research on bacteriophages, which he conducted in the first decade of his research career, immediately after completing medical school. For his part, Burnet made valuable contributions to the understanding of the nature of bacteriophages, a matter of considerable debate at the time he began his work. Reciprocally, it was while working on the phages that Burnet developed the scientific styles, the habits of mind and laboratory techniques and practices that characterized him for the rest of his career. Using evidence from Burnet's published work, as well as personal papers from the period he worked on the phages, this paper demonstrates the direct impact that his experiments with phages had on the development of his characteristic scientific style and approaches, which manifested themselves in his later career and theories, and especially in his thinking regarding various immunological problems.     

Mechanisms of curcumin-induced apoptosis of Ehrlich's ascites carcinoma cells.

Curcumin, the active ingredient from the spice turmeric (Curcuma longa Linn), is a potent antioxidant and anti-inflammatory agent. It has been recently demonstrated to possess discrete chemopreventive activities. However, the molecular mechanisms underlying such anticancer properties of curcumin still remain unrealized, although it has been postulated that induction of apoptosis in cancer cells might be a probable explanation. In the current study, curcumin was found to decrease the Ehrlich's ascites carcinoma (EAC) cell number by the induction of apoptosis in the tumor cells as evident from flow-cytometric analysis of cell cycle phase distribution of nuclear DNA and oligonucleosomal fragmentation. Probing further into the molecular signals leading to apoptosis of EAC cells, we observed that curcumin is causing tumor cell death by the up-regulation of the proto-oncoprotein Bax, release of cytochrome c from the mitochondria, and activation of caspase-3. The status of Bcl-2 remains unchanged in EAC, which would signify that curcumin is bypassing the Bcl-2 checkpoint and overriding its protective effect on apoptosis.