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

Pathogen Recognition and Innate Immunity

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a world...

/pdf/safety-and-efficacy-of-the-bnt162b2-mrna-covid-19-vaccine-kz6rahelgo.pdf

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.

The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

/pdf/cancer-related-inflammation-ltml0xgfd3.pdf

Cancer-related inflammation.

http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

Myeloid leukemia M1 cells can be induced for growth arrest and terminal differentiation into macrophages in response to interleukin 6 (IL-6) or leukemia inhibitory factor (LIF). Recently, a large number of cytokines and growth factors have been shown to activate the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. In the case of IL-6 and LIF, which share a signal transducing receptor gp130, STAT3 is specifically tyrosine-phosphorylated and activated by stimulation with each cytokine in various cell types. To know the role of JAK-STAT pathway in M1 differentiation, we have constructed dominant negative forms of STAT3 and established M1 cell lines that constitutively express them. These M1 cells that overexpressed dominant negative forms showed no induction of differentiation-associated markers including Fc gamma receptors, ferritin light chain, and lysozyme after treatment with IL-6. Expression of either c-myb or c-myc was not downregulated. Furthermore, IL-6- and LIF-mediated growth arrest and apoptosis were completely blocked. Thus these findings demonstrate that STAT3 activation is the critical step in a cascade of events that leads to terminal differentiation of M1 cells.

https://www.pnas.org/content/pnas/93/9/3963.full.pdf

STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line

MyD88 is an adaptor molecule essential for signaling via the Toll-like receptor (TLR)/IL-1 receptor family. TLR4 is a member of the TLR family and a point mutation in the Tlr4 gene causes hyporesponsiveness to lipopolysaccharide (LPS) in C3H/HeJ mice. We have previously shown that both TLR4- and MyD88-deficient mice are hyporesponsive to LPS. In this study we examined the responsiveness of these two knockout mice to various bacterial cell wall components. Cells from TLR4-deficient mice responded to several kinds of LPS, peptidoglycan and crude cell wall preparation from Gram-positive bacteria and mycobacterial lysates. In contrast, macrophages and splenocytes from MyD88-deficient mice did not respond to any of the bacterial components we tested. These results show that MyD88 is essential for the cellular response to bacterial cell wall components.

/pdf/cellular-responses-to-bacterial-cell-wall-components-are-2tgqvl8vai.pdf

Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades.

STAT (signal transducers and activators of transcription) proteins are activated in response to a large number of cytokines, growth factors, and hormones. Upon activation following the binding of ligands to their receptors, STAT proteins dimerize, translocate to the nucleus, and bind to the promoters of specific target genes. To date, seven mammalian members of the STAT family have been identified. Although some cytokines and growth factors can activate multiple STAT proteins, some STATs are activated with considerable specificity. The physiological role of each individual STAT protein is now being examined through the study of "knockout" mice, harboring a null allele for the particular gene. STAT1-deficient mice exhibit a selective signaling defect in response to interferons. STAT4 and STAT6 are essential for Thl-and Th2-responses, respectively. STAT5a-deficient mice exhibit defective mammary gland development. A study of STAT5b-deficient mice indicates that STAT5b mediates the sexually dimorphic effects of growth hormone in the liver. STAT5a and 5b also play different biological roles in the immune system. STAT3-deficient mice die during early embryogenesis, but the role of STAT3 in adult tissues can be assessed by utilizing the CreloxP recombination system to ablate the gene later in life. Analyses of tissue-specific STAT3-deficient mice indicate that STAT3 plays a crucial role in a variety of biological functions, including cell growth, suppression of apoptosis, and cell motility.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.170138

Functional Roles of STAT Family Proteins: Lessons from Knockout Mice

The Toll-like receptors (TLRs) are recently discovered germline-encoded receptors on APCs that are critically important in innate immune recognition of microbial pathogens. However, their role in solid-organ transplantation is unknown. To explore this role, we employed a skin allograft model using mice with targeted deletion of the universal TLR signal adaptor protein, MyD88. We report that minor antigen-mismatched (HY-mismatched) allograft rejection cannot occur in the absence of MyD88 signaling. Furthermore, we show that the inability to reject these allografts results from a reduced number of mature DCs in draining lymph nodes, leading to impaired generation of anti-graft-reactive T cells and impaired Th1 immunity. Hence, this work demonstrates that TLRs can be activated in a transplant setting and not solely by infections. These results link innate immunity to the initiation of the adaptive alloimmune response.

/pdf/critical-role-of-the-toll-like-receptor-signal-adaptor-1zak1zcjut.pdf

Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection

Toll receptors in insects, mammals and plants are key players that sense the invasion of pathogens. Toll-like receptors (TLRs) in mammals have been established to detect specific components of bacterial and fungal pathogens. Furthermore, recent evidence indicates that TLRs are involved in the recognition of viral invasion. Signalling pathways via TLRs originate from the conserved Toll/IL-1 receptor (TIR) domain. The TIR domain-containing MyD88 acts as a common adaptor that induces inflammatory cytokines; however, there exists a MyD88-independent pathway that induces type I IFNs in TLR4 and TLR3 signalling. Another TIR domain-containing adaptor, TIRAP/Mal has recently been shown to mediate the MyD88-dependent activation in the TLR4 and TLR2 signalling pathway. Thus, individual TLRs may have their own signalling systems that characterize their specific activities.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1462-5822.2003.00264.x

Shizuo Akira

Papers

STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line

Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades.

Functional Roles of STAT Family Proteins: Lessons from Knockout Mice

Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection

Toll receptors and pathogen resistance