Encyclopedia of Parasitology

2016 Edition
| Editors: Heinz Mehlhorn

Immune Responses

Reference work entry
DOI: https://doi.org/10.1007/978-3-662-43978-4_1583

A general feature of many parasitic infections by  protozoa or helminths is their chronicity and several reasons contribute to this, e.g., weak  innate immunity and the capacity of parasites to withstand or to evade destruction by specific immune responses of the vertebrate host. General aspects of the various host immune responses are described in the following. Peculiarities of the immunological response to specific parasites are described in detail under the headwords of the respective diseases.

Innate Immunity

The skin and the linings of the respiratory, gastrointestinal, and urogenital tract present formidable physical and chemical barriers to infective organisms and represent a first line of defense. These barriers provide a  natural resistance, also called innate immunity, to infection, but they are not perfect. Protozoan and helminthic parasites, have evolved in such a way that they either are able to penetrate the body’s barriers directly or are transmitted by insect bites.

In the body the alternative pathway of complement activation provides a first line of defense against many parasites. The complement component C3 is cleaved spontaneously in plasma to produce C3b; once bound to the parasite surface and stabilized to form a C3 convertase, activation of the terminal complement components C5-C9 takes place, and the parasites are lysed by the major attack complex MAC. A second line of defense is provided by macrophages and neutrophilic leukocytes, which play a major role in all stages of host defense. These cells by means of their CR3-receptors are able to recognize microbial substances and thus ingest the parasites. In addition, Toll-like receptors (TLRs) have been defined as important transmembrane receptors that confer a certain degree of specificity to the cells of innate immune system. TLRs have been implicated in recognition of every known category of pathogen that causes infectious disease. TLRs can recognize minute concentrations of microbial components and orchestrate an early defense, largely dependent on the MyD88-dependent activation of NF-kB, which will trigger microbiostatic/microbicidal effector mechanisms and lead to the production of proinflammatory cytokines thereby also shaping the adaptive immune response. The importance of the TLR-mediated signaling pathways in the host resistance and pathogenesis during parasitic diseases has been demonstrated by experimental infections of MyD88-deficient mice with various protozoan parasites and helminths. The identification of a single TLR involved in the in vivo host responses to protozoan parasites has been a more difficult task, because protozoan parasites might be recognized by more than one TLR. Nevertheless, a number of distinct molecules derived from protozoan parasites have been shown to activate cells from the innate immune system via TLRs, e.g., glycosylphosphatidinositol anchors from parasite surface proteins are recognized by TLR2, nucleic acids by TLR3 and TLR9, and a profiling-like protein of Toxoplasma gondii by TLR11, respectively. As a result of the TLR-stimulation and the parasite uptake, the secretion of cytokines by phagocytes is initiated which include interleukin-1 (IL-1), IL-6, IL-8, IL-12, and tumor necrosis factor (TNF). These factors recruit more phagocytes to the site of the infection and an increase in circulating neutrophils. Phagocytes also release other proteins with significant local effects, such as oxygen radicals, peroxides,  nitric oxide, prostaglandines, leukotriens, complement components, etc. Infection of cells with viruses, but also with parasites induced the production of interferon (IFN)-α and -β. These interferons contribute to the inhibition of natural killer cells (NK-cells), cells which are known to function in the initial phase of infection with intracellular pathogens, including parasites such as  Leishmania. Activated NK-cells secrete large amounts of IFN-γ. This IFN-γ is critical for the control of some parasitic infection before T cells have been triggered to liberate this cytokine. A further effect of IFN-α and -β is to augment the expression of MHC class I molecules, which favors the ability of host cells to present parasite antigenic peptides to CD8+ cells (see below). Once parasites have survived the innate immune response, the  acquired immunity comes into effect.

Acquired Immunity

Acquired immunity is mediated by the humoral and cellular immune system, in which the B-lymphocytes are mediators of the humoral responses. Upon direct recognition of the parasites, i.e., antigen, they produce antibodies of different isotypes, that are specific for the antigen. A remarkable difference between bone marrow-derived B and thymus-derived T cells is the inability of T cells to recognize antigens directly as B cells do. T cells, on the other hand, need adequate presentation of antigens mostly by major histocompatibility complex (MHC) molecules expressed on antigen-presenting cells (APCs), such as dendritic cells, Langerhans cells, macrophages, B cells, and vascular endothelial cells. The T-cells are distinguished according to their T cell-receptor (TCR) and accessory molecules. The TCR is composed of an α and β chain or an γ and δ chain. Accessory molecules are the CD4 or the CD8 marker.

Antigen Presentation

Before further discussing the functions of the T cells, interest will be focused on the MHC and antigen presentation. MHC genes are organized in a gene complex of about 3.5 mb on chromosome six in man. Several classes of molecules are encoded in this gene complex, of which the MHC class I and class II molecules are central to antigen presentation. MHC class I molecules are formed by a variable polypeptide chain and a constant β-2 microglobulin. The MHC class II molecules represent heterodimers composed of variable α and β chains. Association of antigen with MHC molecules occurs inside the antigen-presenting cell and processing of foreign antigen to peptide fragments is an essential prerequisite for successful association and presentation. The complex of the MHC molecule and antigen peptide is transported to the cell surface and presented to T cells. MHC class I and II molecules can be subdivided into classical and nonclassical MHC molecules. Classical class I molecules are encoded in man by the HLA-A, -B, and -C genes. These highly polymorphic molecules present processed peptides to CD8+ T cells. Nonclassical class I molecules are much less polymorphic and are encoded by HLA-E, -F, and -G. Their function in man is still ill-defined. In the mouse, the related Qa-1 and Qua-2 molecules present a restricted set of peptide antigens, for instance a fragment of lysteriolysin, to CD8+ T cells. Classical MHC class II molecules in man are encoded by HLA-DP, -DQ, and -DR. These molecules present processed peptides to CD4+ T cells. Nonclassical class II molecules, such as DMA and DMB, appear to support classical class II molecules in antigen presentation.

CD1 molecules form a non-MHC-encoded family of molecules involved in antigen presentation. As class I molecules, they are composed of a polymorphic α chain and β2-microglobulin. So far, the isoforms CD1 a-e have been described in humans. Recently, it became apparent that CD1 molecules act as restriction elements in the presentation of several mycobacterial lipids, such as mycolic acid, and glycolipid antigens, such as lipoarabinomannan to T cells. Interestingly, CD1 molecules seem to present nonpeptide antigens not only to classical T cells but also to the recently described subsets of CD4+ NKT 1. 1+ and CD4− CD8− NK 1. 1+ T cells, that are also designated as natural killer T cells or NKT-cells. These NKT-cells, because of their capacity to produce interleukin four and other cytokines, can potentially influence the phenotype of the immune response to class II-restricted antigens. Their role in parasite infection, however, is still unclear.

Whether an antigen will be processed and presented with class I or class II MHC molecules appears to be determined by the route that the antigen takes to enter a cell. Exogeneous antigen is produced outside of the host cell and enters the antigen-presenting cells, which degrade the exogenous protein within the phagosome into peptides of 12–15 amino acids length. The peptides are loaded into the cleft within the MHC class II molecules. The MHC class II peptides complex is then exported to the cell surface, where it is recognized by T-cells displaying CD4. CD4+ T cells recognize their antigen MHC class II restricted. Endogenous antigen is produced within the host cell itself. It is either of host cell or of parasite origin. In the cytosol, proteasomes degrade endogenously synthesized proteins to peptides, which are then transported by particular transport-associated proteins, so-called TAPs to the endoplasmic reticulum. Here the peptides bind to MHC class I molecules. Thereafter the complex is exported to the cell surface. T cells displaying CD8 recognize the complex and are thereby stimulated. Therefore, they are said to be MHC class I restricted.

The great polymorphism of genes coding for MHC molecules allows man to bind and present a vast diversity of different peptides produced by the many parasite pathogens, to a large T cell repertoire, resulting in highly specific immune response.

T-Cell Mediated Responses

Next, the various T cells, to which antigen is presented will be discussed. In man, the T cell population in the periphery amounts to more than 1012 cells, of which more than 90 % carry the α/β T-cell receptor (TCR) and less than 10 % the g/d receptor. The TCR associates with the variable region of the MHC-molecule which carries the antigenic peptide and the CD4 or CD8 molecules bind to the constant regions of the MHC molecules. Binding of the antigen/MHC-complex to the TCR results in the engagement of the CD3-complex, with subsequent signal transduction and T cell activation. This signal transduction is modulated by costimulatory effects induced by the accessory receptor/ligand pairs CD40/CD40 ligand or B7/CD28. CD40-mediated signals seem to affect primariliy CD4+ T cells of the Th1 subtype, whereas the B7 costimulis trigger T cells of the Th2 subtype. The CD4+ T-cells according to their cytokine secretion pattern have been first subdivided by Tim Mossmann into the Th1 and Th2 family, Th1 cells producing IL-2 and IFN-γ, cytokines that serve as stimuli of T-cells or macrophages respectively, and Th2 cells producing IL-4, IL-5, and IL-10, that is T-cells that act as true helper cells for  B-cells. The Th1 cells, via IFN-γ, seem to act as classical cells of delayed type of hypersensitivity, i.e., of cell-mediated immunity for instance in the tuberculin reaction. Thus, they are of prime importance in the control of intracellular microorganisms such as toxoplasma, leishmania, mycobacteria, and others. By virtue of their IFN-γ production Th1 cells also downregulate Th2 cells. The Th2 cells, on the other hand represent the classical T helper cells, which are involved in the allergic reaction and in humoral immune responses. IL-4 is central to IgE production and IL-5 to IgA production and IL-10 downregulates Th1 cells. The subdivision of CD4+ T cells in Th1 and Th2 cells should however not be taken too strictly because during a developing immune response, T cells producing both Th1 and Th2 cytokines are found, and Th1 and Th2 cells might well coexist in the tissue.

Differentiation of Th0 cells into Th1 or Th2 is driven by cytokines produced by different cells of the immune system. IL-12 is the major player in the Th1 pathway and IL-4 driving the Th2 cells. Undoubtedly, the signals which in leishmaniasis are decisive for the initiation of a protective Th1 response versus a disease-promoting Th2 response, are by far not clear.

Besides CD4+ T cells, CD8+ cells are involved in immune reactions to most if not all intracellular parasites including plasmodia, toxoplasma, and leishmania. CD8+ cells function by their capacity to act as cytolytic killer cells as well as producers of cytokines such as IFN-γ, etc. CD8+ T cells lyse infected target cells by cell-to-cell contact subsequent to the recognition of the target peptide that is presented by class I molecules. Target cell lysis is mediated by two separate mechanisms. The first mechanism involves the secretion of perforins and granzymes by the killer cells, which both lead to osmotic lysis of the target cells. The second mechanism requires the cross-linking of the Fas-ligand and the cytolytic CD8+ cells with the Fas-antigen on the target cells with subsequent chromatin condension, DNA fragmentation, and cell rupture. This mechanism induces  apoptosis, also known as programmed cell death, in the target cells. Cytolytic activity is most prominent in CD8+ T cells, however also some CD4+ T-cells have been shown to act as killer cells as in the case of   Toxoplasma gondii -infected macrophages. CD8+ cells may act in synergy with Th1 cells, when Th1 cells produce the cytokines IL-2 and IFN-γ and CD8+ cells contribute their cytolytic activity to the pathogen-eliminating process. Another type of T cells involved in the regulation of antiparasitic immunity are regulatory T cells (Treg). Several types have been described based on their origin, generation, and mechanism of action, with two main subsets identified: “natural” Foxp3+CD4+CD25+ Treg, which develop in the thymus and regulate self-reactive T cells in the periphery, and “inducible” Treg (e.g., Tr1 or Th3 cells), which can develop in the periphery from conventional CD4+ T cells. Both types of Treg, by virtue of their capacity to control the intensity of effector responses, have been shown to play a major role in the control of various parasitic infections.

Specific Aspects of Immune Responses to Helminths

Worms such as nippostrongylus, filaria,  ascaris, and schistosomes induce high levels of specific IgE antibodies and eosinophilia. This characteristic response pattern is caused by the particular ability of helminths to preferentially stimulate the Th2 subset of CD4+ cells, which secrete the cytokines IL-4 and IL-5, IL-4 involved in the production of IgE antibodies and IL-5 acting as growth factor for eosinophils. In vitro studies suggest that helminths opsonized with specific IgE antibodies are lysed by eosinophils that carry Fc receptors specific for IgE, the toxic product contained in the major basic protein of the eosinophils granules. This effector mechanism however does not relate to cell helminths infections as immunity to schistosoma induces Th1 cells and the production of IFN-γ, which results in activation of macrophages that directly delete the schistosome larvae by means of  nitric oxide (NO).

Strategies of Evasion of Immune Mechanisms by Parasites

The capacity of parasites to survive and to persist in their hosts is a result of coevolutionary events that enable the parasites to evade immune effector mechanisms. Most parasites have developed multiple  evasion strategies to circumvent both innate and acquired defense mechanisms of the host, which will be discussed separately for each parasite.

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© Springer-Verlag Berlin Heidelberg 2016