AIDSWEEKLY Plus, 6 May 1996 issue; Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588
Daniel J. DeNoon, Senior Editor

The innate immune system - which emerged with the first multicellular organisms - is not just an old fossil.

Once thought to be the unnecessary vestigial tail of the immune system, new findings show that innate immunity is the cornerstone of the body's ability to fight infection.

This new understanding of immunity has implications for prophylactic and therapeutic manipulations of the immune system to fight bacterial, protozoan, viral, and autoimmune diseases.

"Mammalian innate immunity is not merely a vestige of ancient antimicrobial systems that have been made redundant by the evolution of acquired immunity," argue Douglas T. Fearon of the University of Cambridge, U.K., and Richard M. Locksley of the University of California, San Francisco. "Rather, it dictates the conduct of the acquired immune response."

Fearon and Locksley presented their argument in the journal Science ("The Instructive Role of Innate Immunity in the Acquired Immune Response," Science, 1996;272:50-54).

Innate immunity uses proteins encoded in an organism's germ line to detect potentially dangerous substances, usually carbohydrates. Its chief soluble protein effector is complement, which is activated under two conditions:

* When its classical pathway is triggered by the binding of the molecules known as collectins to certain carbohydrates, or

* When its alternative pathway is triggered by particles rich in carbohydrates but lacking sialic acid.

"Innate immunity has divided the universe into innocuous and potentially noxious substances according to their particular carbohydrate structures," Fearon and Locksley wrote. "Recognition of carbohydrates may have evolved because these common constituents of microbial cell walls have functions, and thus structures, that are distinct from those of carbohydrates of eukaryotic cell surfaces."

Acquired immunity, on the other hand, evolved only in the last 400 million years and exists only in fish, amphibians, reptiles, birds, and mammals. Its role is to respond to new pathogens by its nearly infinite adaptability: the T and B lymphocytes of the acquired immune can rearrange the elements of their immunoglobulin and T-cell receptor genes to create up to 100 billion different clones with distinct antigen receptors.

Once acquired immunity has dealt with a pathogen, some antigen-specific clones remain as memory cells that mediate a more rapid response the next time the pathogen is encountered.

"This quality of memory enables acquired immunity to construct, by selective processes that have an immediate rather than evolutionary time scale, hard-wired responses that are appropriate for contemporary infectious agents," Fearon and Locksley wrote.

Because acquired immunity thus appears to create its own rapid response capability, innate immunity is usually seen as outmoded. But Fearon and Locksley dispute this view.

"In adopting this strategy for coping with the genetic variability of microorganisms, however, acquired immunity has sacrificed a cardinal characteristic of innate immunity; the inherent ability to distinguish between potential pathogens that require an immune response, and innocuous substances for which an immune response is either unnecessary or, in the example of self-antigen, injurious," they wrote.

"Here we show that cellular and soluble components of innate immunity provide instruction that enables the acquired immune response to select appropriate antigens and the strategies for their elimination."

The authors argue that it is the innate immune system that determines which antigens activate T helper cells. This occurs by two processes:

* by selection of proteins for endocytosis by antigen- presenting cells, and

* by augmenting the expression of the B7 costimulatory molecules.

Moreover, complement - a feature of innate immunity - helps shape the antibody responses of B cells by binding to the CD21 portion of the CD19/CD21 receptor complex.

"CD19 is required for a normal antibody response to antigens that are dependent on the interaction of B cells with T helper cells, and amplifies signaling by membrane immunoglobulin through its capacity to bind intracellular proteins," Fearon and Locksley wrote. "This function necessitates the cross-linking of CD19 to membrane immunoglobulin, and complement can serve this purpose by covalently attaching the C3d fragment of the C3 protein to microbial carbohydrate antigens."

The authors also argue that innate immunity determines whether acquired immunity will attack microbes with type 1 (cellular) or type 2 (humoral) responses.

They turn to viruses to help prove their point, arguing that communication between the innate and acquired immune systems must be important since viruses work so hard to interrupt this communication.

"Viruses have also coopted aspects of the complement system to enhance infectivity," they noted.

Fearon and Locksley suggest that manipulation of innate immunity could be the basis of a variety of therapeutic interventions.

"Upregulation of CD1d to create ligands for natural T cells may suppress autoimmune diseases mediated by type 1 responses," they suggested. "Proteins that microorganisms use to subvert innate immunity, such as soluble cytokine receptors and complement inhibitors, are potential targets for acquired immune responses. Effective vaccines may be developed by attachment of C3d or carbohydrates to these antigens to target them to receptors on B cells, macrophages, and dendritic cells."

The corresponding authors for this study are D.T. Fearon, Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 2SP, U.K.; and R.M. Locksley, Department of Medicine, University of California, San Francisco, P.O. Box 0654, C-443, 521 Parnassus Avenue, San Francisco, California 94143-0654.

Copyright (c) 1995 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.

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Copyright © 1996 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.