Nanomedicine, Volume IIA: Biocompatibility

© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003 Nonspecific (Innate) Immune Response

The nonspecific-response branch of the immune system is “innate” in the sense that the human body is born with the inherent ability to recognize certain foreign materials automatically. The innate response occurs to the same extent however many times an infectious agent is encountered. Besides purely mechanical mechanisms or barriers such as skin and mucous membranes, the nonspecific-response branch of the immune system has three major components – complement, phagocytes, and NK (natural killer) cells.

The first component of the nonspecific immune response is complement (Section, a set of ~20 bloodstream proteins that operate in a functional cascade (with one protein activating the next protein) to directly identify and destroy microbial invaders.* These proteins influence the inflammatory process and serve as the primary mediator in the antigen-antibody reactions of the B-cell mediated immune response (see below). With just a few exceptions, proteins of the complement system are designated with the letter “C” – e.g., C2, C3, C4a, C5, and so forth. Once activated, one of the main functions of the complement cascade is to assemble a multi-component biomolecular product called the membrane attack complex (MAC) that renders bacterial cell walls porous, leading to cell death – the MAC is directly bactericidal [234]. The system is highly regulated and there are counter-regulatory proteins to ensure it is not indiscriminately activated.

* Other innate-system antimicrobial peptides are commonly employed by different animal and plant species [2551].

The second component of the nonspecific immune response is the phagocytic cells, comprised of monocytes, macrophages (activated monocytes), and neutrophils (Section For example, macrophages are tissue-resident large phagocytic white cells equipped with chemical receptors sensitive to the polysaccharides found in bacterial cell walls. The receptors enable macrophages to recognize, then engulf and destroy, these bacteria. Upon encountering an invading microbe that is otherwise invisible to the complement system, macrophages can also secrete cytokines (Section, soluble mediators such as interleukin-6 (IL-6), alpha- and beta-interferon, and tumor necrosis factor (TNF) that activate other immune cells. One of the functions of IL-6 is as a signaling protein that instructs the liver to secrete a second signaling protein that in turn binds to mannose residues present on bacterial surfaces. This renders the microbe visible to the complement system and triggers the complement cascade. Macrophages also act as antigen-presenting cells (MHC class II; Section Bloodstream-resident phagocytic cells such as neutrophils (the predominant leukocyte found in pus) have receptors for complement and immunoglobulin. Neutrophils are recruited to the scene of inflammation and assist the macrophages in the digestion of microbial invaders. Basophils, another granulocytic white cell, have an important role in nonspecific inflammation – particularly the release of histamine [5926] and other biochemicals such as IL-4 and IL-13 [5927] that act on blood vessels. Eosinophils moderate the immune response and are closely associated with IgE antibodies, parasitic infections (specifically helminthic), antibody-dependent cell-mediated cytotoxicity (ADCC), and immediate-type hypersensitivity (allergic) reactions [5491]. Macrophages also recognize and ingest “self” cells undergoing apoptosis (Section in vivo, protecting tissues from the toxic contents of dying cells and modulating macrophage regulation of inflammatory and immune responses [5506, 5765-5767].

The third component of the nonspecific immune response is the specialized white blood cells called large granular lymphocytes (LGL) or natural killer (NK) cells [2167-2169]. NK cells are granular lymphocytes slightly larger than B or T cells (Section that can kill some microbes and virus-infected cells, and some types of tumor cells. The “natural” part of their name indicates that they are ready to kill their target cells as soon as they are formed [361], rather than requiring the maturation and education process needed by B cells and T cells (Section NK cells kill by inducing nuclear fragmentation resulting in cell death (apoptosis; Section or by releasing perforin protein which creates holes in the target cell membrane. NK cells do not directly threaten diamondoid-based medical nanorobots except possibly during cytocarriage (Section 9.4.2). In this situation, the apoptotic activity of NK cells can be prevented by expression of a signal or leader peptide (derived from the polymorphic classical major histocompatibility molecules HLA-A, HLA-B and HLA-C) bound to an HLA-E class I MHC molecule at the (cytocarriage vehicle) cell surface. This HLA-E molecule interacts with an NK cell-surface lectin receptor (CD94/NKG2A/B/C) and delivers an inhibitory signal to the NK cell [2357-2359]. The HLA-E molecule is released from nanorobot stores or manufactured (Chapter 19) onboard.


Last updated on 30 April 2004