Selective macroautophagy for immunity.

Macroautophagy was thought to be an unspecific bulk degradation process. However, Ponpuak et al. (2010) show in this issue of Immunity that cytosolic proteins are selectively recruited to autophagosomes to become metabolized to bactericidal peptides.

Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis.

Objective: The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CISs), and to evaluate their potential value in predicting conversion to MS.

Methods: Immune responses to Epstein-Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls.

Results: Compared with controls, CIS patients showed increased humoral (p < 0.

Antiviral immune response in patients with multiple sclerosis and healthy siblings.

The objective of this study was to determine the immune responses to candidate viral triggers of multiple sclerosis in patients and healthy siblings raised in the same family household. Virus antigen-specific IgG responses to Epstein-Barr virus-derived gene products as well as to human herpersvirus-6, human cytomegalovirus, and measles virus were evaluated in 25 multiple sclerosis patients and compared with 49 healthy full-siblings. IgG responses to the latent Epstein-Barr virus-encoded nuclear antigen-1 (EBNA1) were selectively increased in individuals with multiple sclerosis compared with their unaffected siblings.

Antigen processing via autophagy--not only for MHC class II presentation anymore?

T cells monitor intracellular and extracellular protein composition via proteolytic products that are displayed to them on major histocompatibility complex (MHC) molecules. For this purpose it has been documented that MHC class II molecules, which were originally thought to just display lysosomal products of endocytosed proteins to CD4(+) helper T cells, can also present intracellular substrates of autophagic pathways. This has triggered the interest of immunologists into the role of autophagy in antigen processing in general, and recently additional autophagic mechanisms for intracellular and extracellular antigen processing onto MHC class I molecules for presentation to CD8(+) cytolytic T cells have been revealed.

Autophagy-mediated antigen processing in CD4(+) T cell tolerance and immunity.

Macroautophagy, a homeostatic process that shuttles cytoplasmic constituents into endosomal and lysosomal compartments, has recently been shown to deliver antigens for presentation on major histocompatibility complex (MHC) class II. Autophagy-mediated antigen processing in thymic epithelial cells has been suggested to be involved in the generation of a self-MHC restricted and self-tolerant CD4(+) T cell repertoire. Furthermore, there is accumulating evidence that the up-regulation of autophagy by pattern-recognition receptor signaling represents an innate defense mechanism against intracellular pathogens.

Targeting Beclin 1 for viral subversion of macroautophagy.

We have recently characterized that influenza A virus blocks autophagosome degradation via its matrix protein 2. Matrix protein 2 seems to achieve this macroautophagy inhibition not by its well-characterized proton channel function, but possibly due to its binding to Atg6/Beclin 1, thereby enhancing the death of its host cell. Here we discuss several viruses that now have been described to compromise macroautophagy via binding to Atg6/Beclin 1 with different outcomes for their replication, and how interaction with one and the same protein could inhibit autophagosome generation or degradation.

Dysregulated Epstein-Barr virus infection in patients with CIDP.

Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls.

Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes.

Influenza A virus is an important human pathogen causing significant morbidity and mortality every year and threatening the human population with epidemics and pandemics. Therefore, it is important to understand the biology of this virus to develop strategies to control its pathogenicity. Here, we demonstrate that influenza A virus inhibits macroautophagy, a cellular process known to be manipulated by diverse pathogens.

Autophagy in MHC class II presentation of endogenous antigens.

Macroautophagy is a catabolic process for the lysosomal turnover of cell organelles and protein aggregates. Lysosomal degradation products are displayed by major histocompatibility class II molecules to CD4(+) T cells in the steady state for tolerance induction and during infections to mount adaptive immune responses. It has recently been shown that macroautophagy substrates can also give rise to MHC class II ligands.

Morbus Crohn--a disease of failing macroautophagy in the immune system?

Mutations in genes involved in macroautophagy have been found to be associated with Morbus Crohn, also called Crohn's disease (CD), an inflammatory bowel disease. Taking this disease as an example for pathogenesis due to altered macroautophagy, we discuss here how macroautophagy supports innate and adaptive immunity. This support ranges from maintenance of components of the immune system, antigen processing for presentation to the immune system, to education of the immune system in order to distinguish self from dangerous non-self.

Regulatory NK-cell functions in inflammation and autoimmunity.

Natural killer (NK) cells were viewed traditionally as cytotoxic effector cells whose rapid killing of infected and transformed cells without preactivation provides a first line of defense prior to the initiation of an adaptive immune response against infection and tumor development. However, it has become clear that NK cells interact with various components of the immune system, and therefore have the potential to function as regulatory cells. While NK cells can assist in dendritic cell (DC) maturation and T-cell polarization, increasing evidence indicates that NK cells can also prevent and limit adaptive (auto) immune responses via killing of autologous myeloid and lymphoid cells.

Priming of protective T cell responses against virus-induced tumors in mice with human immune system components.

Many pathogens that cause human disease infect only humans. To identify the mechanisms of immune protection against these pathogens and also to evaluate promising vaccine candidates, a small animal model would be desirable. We demonstrate that primary T cell responses in mice with reconstituted human immune system components control infection with the oncogenic and persistent Epstein-Barr virus (EBV).

EBV in MS: guilty by association?

Epstein-Barr Virus (EBV) is one of the most successful human viruses, infecting more than 90% of the adult population worldwide and persisting for the lifetime of the host. Individuals with a history of symptomatic primary EBV infection, called infectious mononucleosis, carry a moderately higher risk of developing multiple sclerosis (MS). In addition, EBV-specific immune responses, which crucially regulate the host-virus balance in healthy virus carriers, are altered in patients with MS.

Antiviral immune responses: triggers of or triggered by autoimmunity?

The predisposition of individuals to several common autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, is genetically linked to certain human MHC class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins, as well as the geographical distribution of disease risk, suggest the involvement of environmental factors in the development of these diseases. Among these environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity.

Dendritic cell interactions with NK cells from different tissues.

Introduction: In recent years, it has been realized that innate lymphocytes do not act in isolation but potentiate their efficiency by interacting with each other, resulting even in the regulation of adaptive immune response. One such cross-talk exists between dendritic cells (DCs) and natural killer (NK) cells. Here, we summarize recent studies on which subsets of these two innate immune components participate in this interaction, how it influences immune responses, and to which extent similar stimuli are integrated by DCs and NK cells during innate immunity.

Monitoring macroautophagy by major histocompatibility complex class II presentation of targeted antigens.

Major histocompatibility complex (MHC) class I and II molecules can both present cytosolic and nuclear antigens to CD8(+) and CD4(+) T cells, respectively. However, MHC class I displays proteasomal, whereas MHC class II molecules display lysosomal, degradation products. One pathway by which intracellular antigens gain access to lysosomal degradation is macroautophagy.

Macroautophagy in immunity and tolerance.

Autophagy and proteasomal degradation constitute the two main catabolic pathways in cells. While the proteasome degrades primarily short-lived soluble proteins, macroautophagy, the main constitutive autophagic pathway, delivers cell organelles and protein aggregates for lysosomal degradation. Both the proteasome and macroautophagy are attractive effector mechanisms for the immune system because they can be used to degrade foreign substances, including pathogenic proteins, within cells.

Enhancing immunity through autophagy.

Next to the proteasome, autophagy is the main catabolic pathway for the degradation of cytoplasmic constituents. The immune system uses it both as an effector mechanism to clear intracellular pathogens and as a mechanism to monitor its products for evidence of pathogen invasion and cellular transformation. Because autophagy delivers intracellular material for lysosomal degradation, its products are primarily loaded onto MHC class II molecules and are able to stimulate CD4+ T cells.

Children with endemic Burkitt lymphoma are deficient in EBNA1-specific IFN-gamma T cell responses.

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in equatorial Africa and is linked to Epstein-Barr virus (EBV) and Plasmodium falciparum coinfections early in life. Epstein-Barr nuclear antigen 1 (EBNA1) is the sole viral latent antigen expressed in BL tumors. Loss of EBNA1-specific immune surveillance could allow eBL emergence.

The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death.

The antibacterial amino-acid derivative taurolidine (TAU) has been recently shown to exhibit anti-neoplastic activity based on a mechanism, which is still unknown in detail. Cytotoxicity and clonogenic assays were performed and the impact of apoptosis modulators, a radical scavenger, autophagy inhibitors, silencing of apoptosis inducing actor (AIF) and cytochrome-c (Cyt-C) by siRNA, and knockdown of autophagy related genes were evaluated in vitro. The intracellular ATP-content, release of AIF and Cyt-C, and DNA-laddering were investigated.

Immune escape by Epstein-Barr virus associated malignancies.

Persistent Epstein-Barr virus (EBV) infection remains asymptomatic in the majority of virus carriers, despite the potent growth transforming potential of this virus. The increased frequency of EBV associated B cell lymphomas in immune compromised individuals suggests that tumor-free chronic infection with this virus is in part due to immune control. Here we discuss the evidence that loss of selective components of EBV specific immunity might contribute to EBV associated malignancies, like nasopharyngeal carcinoma, Burkitt's and Hodgkin's lymphoma, in otherwise immune competent patients.

Non-cytotoxic protection by human NK cells in mucosal secondary lymphoid tissues.

Even though NK cells have been named for their spontaneous cytotoxicity, a large subpopulation of human NK cells primarily responds to activation with cytokine secretion and not killing. These CD56brightCD16(-) NK cells are abundant in secondary lymphoid tissues, can restrict pathogens that have breached mucosal barriers, and assist Th1 polarization during immune response priming. This exciting new aspect of NK-cell biology is discussed in this viewpoint.