Immunology of Invertebrates: Humoral

Abstract

Phagocytosis in unicellular animals represents a ubiquitous form of immune defence. Multicellular invertebrates possess phagocytotic cells and have evolved more complex functions attributed to immune defence, for example opsonisation, encapsulation, melanisation and specialised humoral immune response. Thus, all animals possess innate, natural, nonspecific, nonanticipatory, nonclonal, germline host defence functions. Pathogen‐associated molecular pattern (PAMPs) are conserved structures or motifs of microbes and are recognised by different families of pattern recognition proteins (Toll pathway, cascade of serine proteases, agglutinins/lectins), thereby activating an immunological response of the host. This enhanced specificity conveys a special form of memory in invertebrates. At the humoral response antimicrobial proteins, iron‐binding proteins, phenoloxidase, matrix metalloproteases, small effector molecules (reactive oxygen species and nitrogen intermediates) and complement‐like molecules are synthesised by immuno‐/haemocytes and fat body and released at infectious tissue and into the haemolymph. The communication between and regulation of the humoral immune response is orchestrated by cytokine‐like molecules and protease inhibitors, which also bridge as regulator molecules the humoral with the cellular defence system.

Key Concepts:

  • The phylogenetically ancient innate response attacks infectious DNA/RNA carriers from the moment of first contact and is the fundamental defensive weapon of multicellular organisms.

  • The process of phagocytosis in unicellular organisms represents the most ancient immune defence, followed by opsonisation, encapsulation and melanisation in metazoa.

  • The pathogen‐associated molecular patterns (PAMPs) are conserved structures and motifs of microbes, and, when recognised by pattern recognition receptors (PRRs), initiate an immune response of the host.

  • The nonself‐recognition of PAMPs by PRRs is already a special form of memory of invertebrate hosts.

  • The immune surveillance concept based on self‐ and nonself‐discrimination/recognition is extended and fine‐tuned by the danger model.

  • The important key genes and pathways of vertebrate immunity have much earlier origins and are expressed in some of the simplest of true animals.

  • The invertebrate immunity is an example to understand a Darwinian principle of evolution that complex systems develop through small sequential steps.

Keywords: phagocytosis; opsonisation; melanisation; pathogen‐associated molecular patterns; pattern recognition proteins; Toll‐like receptors; C‐type lectins; antimicrobial peptides; phenoloxidase; iron‐binding proteins

Figure 1.

(a) Three key pathways of innate immunity. In insects, for example Drosophila, two protein families activate intracellular pathways related to the immune response, namely the antimicrobial response (6): the Gram‐negative binding proteins (GNBPs) and the peptidoglycan recognition proteins (PGRPs). Fungi (1), yeast (2) and Gram‐positive bacteria (4) activate the Toll pathway via a cascade of serine proteases leading to the cleavage of Toll ligand Spätzle, a cysteine knot molecule with structural similarities to mammalian neurotrophins and the unpaired‐family Upd1‐3, which induce the JAK/STAT pathway by binding to an interleukin‐6‐related cytokine receptor. In the case of bacterial (4) or yeast (2) infections circulating recognition molecules like peptidoglycan recognition protein–SA (PGRP‐SA/SD) (4) and Gram‐negative‐binding protein 3 (GNBP1‐3) (2,4) bind to peptidoglycan and activate proteolytic cascades (3) to activate Spätzle. Fungal infections (1) seem to induce a protease, called persephone, to cleave Pro‐Spätzle. PGRP‐LC and PGRP‐LE are sensing Gram‐negative bacteria and activate the IMD pathway. The PGRPs are an evolutionary conserved family of microbial recognition proteins defined by a domain with homology to a peptidoglycans‐digesting enzyme, the N‐acetylmuramyl‐l‐alanine amidases. In Drosophila, 13 PGRPs are classified, according to size, localisation and enzymatic activity to activate or inhibit the IMD pathway. After PGRP‐LC binding of peptidoglycan, Imd is cleaved by the caspase Dredd, allowing it to associate with the E3 ligaseDiap2 (5). This results in K63 polyubiquitination leading to cleavage and phosphorylation of the NFκB transcription factor Relish, which enters the nucleus to recruit RNA polymerase II to target gene transcriptions necessary for antimicrobial responses. Imd signalling can be downregulated by the deubiquitinase USP36 (7), by Pirk/PIMS (8) and, in the tsetse fly, by PGRP‐LB (9). The Toll and IMD pathways synergise at the level of transcription factor activation, but are not strictly separated. Both cooperate to produce an appropriate response in many host defence processes, for example antimicrobial peptides (AMPs). The JAK/STAT is activated in Drosophila and Anopheles by cytokines that bind the receptor Domeless, resulting in phosphorylation of the transcription factor STAT by the kinase JAK. STAT dimers are translocated to the nucleus and activate a transcriptional response of those genes involved to cope with stress or injury, to recruit haemocytes to tumours (10) and epithelial renewal in response to gut damage (11) caused by infections (reproduced from Welchman et al. with permission from Elsevier). (b) Up take of the serpin protease by Garland cells, which are invertebrate arthrocytes/nephrocytes with a filtration, slits diaphragma. The Garland cells takes up waste products from the haemolymph. By an endocytosis process, in which extracellular serpin‐family inhibitors are involved, Necrotic (red dye) material is endocytosed via the LpR1‐trafficking receptor, processed through multivesicular bodies, and delivered to the lysosome for degradation. This is an important process of innate immunity in invertebrates, and, interestingly, Garland cells accumulate iron‐loaded ferritin (see also ferritin‐binding proteins). Adapted from Soukup SF, Culi J, and Gubb D (2009) Uptake of the necrotic serpin in Drosophila melanogaster via the lipophorin receptor‐1. PLoS Genetics5: e1000532. Reproduced from Welchman et al. . With permission from Elsevier.

Figure 2.

Schematic representation of the known components of the prophenoloxidase‐activating system. It assumes that the immunocyte (granulocyte) synthesises the inactive form of intracellular prophenoloxidase (proPO) (green granules) and, after degranulation (exocytosis) caused by foreign antigens (e.g. lipopolysaccharide (LPS), β‐1,3‐glucans and peptidoglycans) or injury, releases it into the haemolymph (extracellular). In addition to the proPO, the haemolymph also contains inactive and active serine proteases (also of cuticular origin) and elicitor‐binding proteins, all of which are thought to be involved in the activation of the proPO and its conversion into phenoloxidase (PO; tyrosinase), which eventually produces melanin. Inhibitors of proPO and PO are known to regulate the activation of these two compounds. Note that the immunocyte contains both electron‐dense (red) and electron‐lucent (green) intracellular granules.

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Further Reading

Beck G, Cooper EL, Habicht GS and Marchalonis JJ (eds) (1994) Primoridal Immunity. New York: New York Academy of Sciences.

Egesten A, Schmidt A and Herwald H (eds) (2008) Trends in Innate Immunity. Contribution to Microbiology, vol. 15. Basel: Karger Publisher.

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Zänker, Kurt S(Jun 2010) Immunology of Invertebrates: Humoral. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000522.pub2]