Alistair Cunningham and the generation of antibody diversity <i>after</i> antigen

Steele, Edward J.

doi:10.1038/icb.1992.16

Immunology & Cell Biology

1992

DOI: 10.1038/icb.1992.16

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Alistair Cunningham and the generation of antibody diversity after antigen

Edward J. Steele

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Cited by 4 publications

(1 citation statement)

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“…As powerful as this elegantly simple model was in describing reactivity to antigen, there were a variety of phenomena that could not be explained solely on the basis of eliminating self-reactive cells during ontogeny. The first was the finding that peripheral somatic hypermutation could occur within the B cell compartment which might result in the generation of anti-self specificities, even in the mature immune system (Steele 1992). This problem, in part, was the impetus for the Bretscher/Cohn tiiodei for self/non-self discrimination that could invoke lymphocyte tolerance at any stage of development (Bretscher & Cohn 1970).…”

mentioning

confidence: 99%

Pancreatic Islet Allograft Immunity and Tolerance: the Two‐Signal Hypothesis Revisited

Gill

Coulombe

Lafferty

1996

Immunological Reviews

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The principle assumption of this discussion is that costimulation (CoS) forms the primary stimulus that compels T cells to mount a response to their specific antigen. However, this response can be either positive or negative, depending on the developmental stage of the T cell and the microenvironment in which the antigen and CoS are received. Thus, both immunity and tolerance may represent different outcomes of a two-signal process. We would emphasize that CoS is a functional term and not a strict molecular definition. While many molecular interactions have been described as providing CoS activity, notably those involving the B-7 family of cell surface molecules, it is not yet clear what combination(s) of non-antigen-specific signals may fulfil this function. This point is important because many studies have achieved tolerance through strategies designed to inhibit specific CoS molecules. However, it may be that differential signaling through distinct CoS molecules, rather than a global inhibition of CoS per se, plays a role in the generation of active tolerance in such studies (Bluestone 1995). A corollary of this notion is that antigen (signal 1) delivery to T cells is a null event and so is not an inherently paralysing signal. Of course, if signal 1 is not itself a tolerogenic signal, then other mechanisms are necessary to explain many empirical observations of tolerance to allogeneic or self antigens. This is best illustrated by those forms of functional tolerance to either alloantigens or self antigens that do not appear to be the result of clonal deletion/inactivation. It would be relatively simple to invoke a model of tolerance whereby the relevant tissue-destructive cell is eliminated or inactivated; such a model would preclude the necessity to suggest active regulatory mechanisms of tolerance. However, in several model systems, including our own observations concerning tolerance induction to APC-depleted islet allografts, tissue-destructive T cells can persist in recipients tolerant to allogeneic or self antigens. Furthermore, there are key examples in which tolerance demonstrates a dominant phenotype; that is, tolerant cells can regulate the activity of naive, non-tolerant cells. This latter observation points to the function of an active, regulatory form of tolerance. As such, we would emphasize that tolerance should not be defined as unresponsiveness since the tolerant state is the consequence of very active immune reactions.

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confidence: 99%

Pancreatic Islet Allograft Immunity and Tolerance: the Two‐Signal Hypothesis Revisited

Gill

Coulombe

Lafferty

1996

Immunological Reviews

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Philosophy in the laboratory: The debate over evidence for E.J. Steele's Lamarckian hypothesis

Parascandola¹

1995

Studies in History and Philosophy of Science Part A

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Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures

Steele

2016

DNA Repair

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Alistair Cunningham and the generation of antibody diversity after antigen

Cited by 4 publications

References 17 publications

Pancreatic Islet Allograft Immunity and Tolerance: the Two‐Signal Hypothesis Revisited

Pancreatic Islet Allograft Immunity and Tolerance: the Two‐Signal Hypothesis Revisited

Philosophy in the laboratory: The debate over evidence for E.J. Steele's Lamarckian hypothesis

Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures

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