抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

/pdf/exploring-the-full-spectrum-of-macrophage-activation-b5rnrcgcen.pdf

Exploring the full spectrum of macrophage activation.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(12)61729-2.pdf

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010

The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.

Alternative activation of macrophages

Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.

/pdf/macrophage-plasticity-and-polarization-in-vivo-veritas-3j0n8qsu6m.pdf

Macrophage plasticity and polarization: in vivo veritas

To investigate different factors associated with hookworm infections we conducted 2 studies in a commune in northern Viet Nam. The first was part of a larger study on anaemia and covered 213 women (15-49 years of age) and their 92 children (6 months to 5 years of age) in one commune; 90% of the families reported using human faeces for fertilizer. Women who reported using fresh human faeces as fertilizer had significantly higher hookworm egg counts than women who either used treated human faeces or who did not use human faeces as fertilizer. The second study examined how human faeces were used for fertilizer in 30 selected families. Women participated in preparation and application of human faeces to crops in 81% of the families using human faeces for fertilizer. Two methods of preparing the faeces were described: 48% of the families mixed the faeces with ash before applying them to the field; 18% mixed the faeces with water; 33% used both methods.

The use of human faeces for fertilizer is associated with increased intensity of hookworm infection in Vietnamese women

A CD4+ clone (clone B), characterized as Th1 based on its selective production of IFN-gamma and IL-2, was established from C57Bl/6 mice protectively immunized against Schistosoma mansoni by intradermal vaccination with soluble worm Ags, plus bacillus Calmette Guerin. In agreement with previous results demonstrating an IFN-gamma-dependent cell-mediated protective mechanism in this vaccination model, Ag-elicited peritoneal macrophages from syngeneic recipients of this clone were activated to kill schistosome larvae (schistosomula) in vitro. Moreover, recipients of clone B displayed significant resistance against cercarial challenge. By screening a battery of lambda(gt11) clones from an adult worm cDNA library, one recombinant (25B) was identified that stimulated clone B specifically. Analysis of the 25B cDNA insert revealed a nucleotide sequence identical with that of the large subunit of schistosome calpain, a Ca2+-activated neutral proteinase. By expressing the products of PCR subcloning, we identified a 146-amino acid region of the 25B gene containing immunologic activity equivalent to the whole polypeptide. Overlapping peptides spanning this region were synthesized, and a core epitope was identified with the sequence EWKGAWCDGS. Since clone B responds to supernatants from cultured schistosomula, we postulate that the recognition of calpain released by invading larvae and resulting induction of Th1 cytokines accounts for the protection mediated by the adoptively transferred clone. Our findings thus implicate calpain as a target of protective immunity in schistosomes and provide the first example of a candidate vaccine Ag for this parasite identified on the basis of T cell reactivity.

Calpain is the target antigen of a th1 clone that transfers protective immunity against schistosoma mansoni

Leishmania braziliensis infections are often associated with exaggerated immune responses that can sometimes lead to severe disease associated with high levels of IFN-γ and TNF-α. To explore the role played by dendritic cells (DCs) in these responses, we characterized DCs that were exposed to L. braziliensis. We found that DCs cultured with L. braziliensis parasites up-regulated DC activation markers and produced IL-12 and TNF-α. However, not all DCs in the culture became infected, and an analysis of infected and uninfected DCs demonstrated that the up-regulation of activation markers and IL-12 production was primarily confined to the uninfected (bystander) DCs. Further studies with Transwell chambers and parasite fractions indicated that the activation of bystander DCs was mediated by a soluble parasite product, in a type 1 IFN- and MyD88-independent, but TNF-α-dependent fashion, and that the activated DCs were more efficient at presenting Ag than control DCs. In contrast, L. braziliensis-infected DCs failed to up-regulate activation markers, but exhibited a dramatic enhancement in their ability to produce TNF-α in response to LPS as compared with uninfected DCs. These findings uncover a dual role for DCs in L. braziliensis infection: T cell activation by bystander DCs due to enhanced Ag-presenting capacity following exposure to soluble parasite products, and increased production of TNF-α by infected cells that may contribute to the local control of the parasites, but concomitantly induce immunopathology.

Functional Dichotomy of Dendritic Cells following Interaction with Leishmania braziliensis: Infected Cells Produce High Levels of TNF-α, whereas Bystander Dendritic Cells Are Activated to Promote T Cell Responses

Edward J. Pearce

Papers

The use of human faeces for fertilizer is associated with increased intensity of hookworm infection in Vietnamese women

Calpain is the target antigen of a th1 clone that transfers protective immunity against schistosoma mansoni

Functional Dichotomy of Dendritic Cells following Interaction with Leishmania braziliensis: Infected Cells Produce High Levels of TNF-α, whereas Bystander Dendritic Cells Are Activated to Promote T Cell Responses

Immunology of hepatosplenic schistosomiasis mansoni: a human perspective.

Transgene expression in Schistosoma mansoni: introduction of RNA into schistosomula by electroporation.