Immune defense and host life history

Recent interest has focused on immune response in an evolutionary context, with particular attention to disease resistance as a life-history trait, subject to trade-offs against other traits such as reproductive effort. Immune defense has several characteristics that complicate this approach, however; for example, because of the risk of autoimmunity, optimal immune defense is not necessarily maximum immune defense. Two important types of cost associated with immunity in the context of life history are resource costs, those related to the allocation of essential but limited resources, such as energy or nutrients, and option costs, those paid not in the currency of resources but in functional or structural components of the organism. Resource and option costs are likely to apply to different aspects of resistance. Recent investigations into possible trade-offs between reproductive effort, particularly sexual displays, and immunity have suggested interesting functional links between the two. Although all organisms balance the costs of immune defense against the requirements of reproduction, this balance works out differently for males than it does for females, creating sex differences in immune response that in turn are related to ecological factors such as the mating system. We conclude that immune response is indeed costly and that future work would do well to include invertebrates, which have sometimes been neglected in studies of the ecology of immune defense.     

The tissue-specific self-pathogen is the protective self-antigen: the case of uveitis

Vaccination with peptides derived from interphotoreceptor retinoid-binding protein (a self-Ag that can cause experimental autoimmune uveoretinitis) resulted in protection of retinal ganglion cells from glutamate-induced death or death as a consequence of optic nerve injury. In the case of glutamate insult, no such protection was obtained by vaccination with myelin Ags (self-Ags associated with an autoimmune disease in the brain and spinal cord that evokes a protective immune response against consequences of injury to myelinated axons). We suggest that protective autoimmunity is the body's defense mechanism against destructive self-compounds, and an autoimmune disease is the outcome of a failure to properly control such a response. Accordingly, the specific self-Ag (although not necessarily its particular epitopes) used by the body for protection against potentially harmful self-compounds (e.g., glutamate) can be inferred from the specificity of the autoimmune disease associated with the site at which the stress occurs (irrespectively of the type of stress) and is in need of help.     

Selective targeting of the immune response in autoimmune demyelination.

Recent developments in molecular and cellular immunology have led to the formulation of refined models that describe how tolerance to self-antigens is broken and autoimmunity develops. This knowledge can now be used to develop alternative approaches to conventional immunosuppression for the treatment of autoimmune demyelinating disorders. The ideal therapy would reverse established disease or prevent further progression by selectively eliminating the aggressive effector molecules or cells while leaving the immune system virtually intact. Indeed, several groups are engaged in preliminary or advanced clinical studies of promising specific immunotherapies for multiple sclerosis and other autoimmune conditions. Current data suggest that the immune response that results in organ-specific autoimmunity is highly complex and redundant in humans. This suggests that antigen-specific approaches may be less successful than broader immunotherapeutic strategies for treating multiple sclerosis and related diseases.     

Autoimmunity as a special case of immunity: removing threats from within

The function of the adaptive immune response against exogenous (non-self) agents is to help the innate arm of the immune system (represented by phagocytic cells) to fight and eliminate these agents. We suggest that the body also protects itself against potentially harmful self components using mechanisms similar to those used for fighting and eliminating non-self agents, and that the protective immune activity against self-components competes with the activity of self-destructive compounds. Tolerance to self is thus not a lack of response to self, but the ability to tolerate an active defense response to self without developing an autoimmune disease.     

Loss of autoimmune T cells correlates with brain diseases: possible implications for schizophrenia?

T-cell-mediated autoimmunity participates in physiological defense, maintenance and repair of the adult brain. However, unless such autoimmune responses to insults are rigorously controlled, they might lead to an autoimmune disease or other immune-related defects, where destructive activity outweighs the beneficial effect. Here, we discuss these apparently contradictory effects of autoimmunity in schizophrenic patients, whose typical immune aberrations have prompted recent speculation about an autoimmune-related etiology. We found that, although schizophrenic patients have active immune systems, they often lack autoimmune clones specifically reactive to a major myelin protein, myelin basic protein (MBP). This, in conjunction with our discovery in rodents that T cells that recognize brain-resident proteins are needed for normal cognitive functioning, led us to propose an immune-based neurodevelopmental hypothesis, in which autoimmune-T-cell deficiency is suggested to cause onset or progression of schizophrenia.     

Natural killer cells in human autoimmune disorders

Natural killer (NK) cells are innate lymphocytes that play a critical role in early host defense against viruses. Through their cytolytic capacity and generation of cytokines and chemokines, NK cells modulate the activity of other components of the innate and adaptive immune systems and have been implicated in the initiation or maintenance of autoimmune responses. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in T-cell and B-cell-mediated autoimmune disorders in humans, with a particular focus on multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. A better understanding of the contributions of NK cells to the development of autoimmunity may lead to novel therapeutic targets in these diseases.     

Evolutionarily conserved antigens in autoimmune disease: implications for an infective aetiology

The immune system has evolved to eliminate or inactivate infectious organisms. An inappropriate response against self-components (autoantigens) can result in autoimmune disease. Here we examine the hypothesis that some evolutionarily conserved proteins, present in pathogenic and commensal organisms and their hosts, provide the stimulus that initiates autoimmune disease in susceptible individuals. We focus on seven autoantigens, of which at least four, glutamate decarboxylase, pyruvate dehydrogenase, histidyl-tRNA synthetase and alpha enolase, have orthologs in bacteria. Citrullinated alpha-enolase, a target for autoantibodies in 40% of patients with rheumatoid arthritis, is our main example. The major epitope is highly conserved, with over 90% identity to human in some bacteria. We propose that this reactivity of autoantibodies to shared sequences provides a model of autoimmunity in rheumatoid arthritis, which may well extend to other autoimmune disease in humans.     

Harnessing the immune system for neuroprotection: therapeutic vaccines for acute and chronic neurodegenerative disorders

Nerve injury causes degeneration of directly injured neurons and the damage spreads to neighboring neurons. Research on containing the damage has been mainly pharmacological, and has not recruited the immune system. We recently discovered that after traumatic injury to the central nervous system (spinal cord or optic nerve), the immune system apparently recognizes certain injury-associated self-compounds as potentially destructive and comes to the rescue with a protective antiself response mediated by a T-cell subpopulation that can recognize self-antigens. We further showed that individuals differ in their ability to manifest this protective autoimmunity, which is correlated with their ability to resist the development of autoimmune diseases. This finding led us to suggest that the antiself response must be tightly regulated to be expressed in a beneficial rather than a destructive way. In seeking to develop a neuroprotective therapy by boosting the beneficial autoimmune response to injury-associated self-antigens, we looked for an antigen that would not induce an autoimmune disease. Candidate vaccines were the safe synthetic copolymer Cop-1, known to cross-react with self-antigens, or altered myelin-derived peptides. Using these compounds as vaccines, we could safely boost the protective autoimmune response in animal models of acute and chronic insults of mechanical or biochemical origin. Since this vaccination is effective even when given after the insult, and because it protects against the toxicity of glutamate (the most common mediator of secondary degeneration), it can be used to treat chronic neurodegenerative disorders such as glaucoma, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.     

Local transgenic expression of granulocyte macrophage-colony stimulating factor initiates autoimmunity

Mechanisms leading to breakdown of immunological tolerance and initiation of autoimmunity are poorly understood. Experimental autoimmune gastritis is a paradigm of organ-specific autoimmunity arising from a pathogenic autoimmune response to gastric H/K ATPase. The gastritis is accompanied by autoantibodies to the gastric H/K ATPase. The best characterized model of experimental autoimmune gastritis requires neonatal thymectomy. This procedure disrupts the immune repertoire, limiting its usefulness in understanding how autoimmunity arises in animals with intact immune systems. Here we tested whether local production of GM-CSF, a pro-inflammatory cytokine, is sufficient to break tolerance and initiate autoimmunity. We generated transgenic mice expressing GM-CSF in the stomach. These transgenic mice spontaneously developed gastritis with an incidence of about 80% after six backcrosses to gastritis-susceptible BALBc/CrSlc mice. The gastritis is accompanied by mucosal hypertrophy, enlargement of draining lymph nodes and autoantibodies to gastric H/K ATPase. An infiltrate of dendritic cells and macrophages preceded CD4 T cells into the gastric mucosa. T cells from draining lymph nodes specifically proliferated to the gastric H/K ATPase. CD4 but not CD8 T cells transferred gastritis to nude mouse recipients. CD4(+) CD25(+) T cells from the spleen retained anergic suppressive properties that were reversed by IL-2. We conclude that local expression of GM-CSF is sufficient to break tolerance and initiate autoimmunity mediated by CD4 T cells. This new mouse model should be useful for studies of organ-specific autoimmunity.     

How specific should immunological memory be?

Protection against infection hinges on a close interplay between the innate immune system and the adaptive immune system. Depending on the type and context of a pathogen, the innate system instructs the adaptive immune system to induce an appropriate immune response. Here, we hypothesize that the adaptive immune system stores these instructions by changing from a naive to an appropriate memory phenotype. In a secondary immune reaction, memory lymphocytes adhere to their instructed phenotype. Because cross-reactions with unrelated Ags can be detrimental, such a qualitative form of memory requires a sufficient degree of specificity of the adaptive immune system. For example, lymphocytes instructed to clear a particular pathogen may cause autoimmunity when cross-reacting with ignored self molecules. Alternatively, memory cells may induce an immune response of the wrong mode when cross-reacting with subsequent pathogens. To maximize the likelihood of responding to a wide variety of pathogens, it is also required that the immune system be sufficiently cross-reactive. By means of a probabilistic model, we show that these conflicting requirements are met optimally by a highly specific memory lymphocyte repertoire. This explains why the lymphocyte system that was built on a preserved functional innate immune system has such a high degree of specificity. Our analysis suggests that 1) memory lymphocytes should be more specific than naive lymphocytes and 2) species with small lymphocyte repertoires should be more vulnerable to both infection and autoimmune diseases.     

Plant autoimmunity—fresh insights into an old phenomenon

The plant immune system is well equipped to ward off the attacks of different types of phytopathogens. It primarily relies on two types of immune sensors—plasma membrane-resident receptor-like kinases and intracellular nucleotide-binding domain leucine-rich repeat (NLRs) receptors that engage preferentially in pattern- and effector-triggered immunity, respectively. Delicate fine-tuning, in particular of the NLR-governed branch of immunity, is key to prevent inappropriate and deleterious activation of plant immune responses. Inadequate NLR allele constellations, such as in the case of hybrid incompatibility, and the mis-activation of NLRs or the absence or modification of proteins guarded by these NLRs can result in the spontaneous initiation of plant defense responses and cell death—a phenomenon referred to as plant autoimmunity. Here, we review recent insights augmenting our mechanistic comprehension of plant autoimmunity. The recent findings broaden our understanding regarding hybrid incompatibility, unravel candidates for proteins likely guarded by NLRs and underline the necessity for the fine-tuning of NLR expression at various levels to avoid autoimmunity. We further present recently emerged tools to study plant autoimmunity and draw a cross-kingdom comparison to the role of NLRs in animal autoimmune conditions.

Increasing evidence indicates that plant autoimmunity is in many cases the consequence of the inappropriate activation of cytoplasmic immune sensors.     

Autoreactive T cells mediate NK cell degeneration in autoimmune disease

Emerging evidence indicates that NK cells play an important and complex role in autoimmune disease. Humans with autoimmune diseases often have reduced NK cell numbers and compromised NK cell functions. Mechanisms underlying this NK cell degeneration and its biological significance are not known. In this study we show that, in an experimental model of human autoimmune myasthenia gravis induced by a self-Ag, the acetylcholine receptor, NK cells undergo proliferation during the initiation of autoimmunity, followed by significant degeneration associated with the establishment of the autoreactive T cell response. We show that NK cell degeneration was mediated by IL-21 derived from autoreactive CD4(+) T cells, and that acetylcholine receptor-immunized IL-21R-deficient mice, with competent NK cells, developed exacerbated autoimmunity. Thus, NK cell degeneration may serve as a means evolved by the immune system to control excessive autoimmunity.     

Lack of chromatin and nuclear fragmentation in vivo impairs the production of lupus anti-nuclear antibodies

Nuclear autoantigens in systemic lupus erythematosus are thought to derive primarily from apoptotic cells, yet there is no direct evidence that interfering with apoptosis impairs the generation of lupus autoantibodies. Here we use a mouse model that lacks the endonuclease caspase-activated DNase (CAD), resulting in an absence of chromatin and nuclear fragmentation during apoptotic cell death. We show that in this mouse, production and release into circulation of chromatin is impaired after exposure to several apoptotic triggers, but that the absence of CAD does not interfere with upstream steps of apoptosis or immune system function. Finally we show that in CAD-mutant mice, impaired lupus autoimmunity is skewed toward known cytoplasmic components, and autoimmunity toward membrane autoantigens is preserved, while autoimmunity toward chromatin and other lupus nuclear targets is severely impaired or absent. We also show, as control, that the induction of experimental autoimmune encephalomyelitis is not affected by the absence of CAD. Thus, our work in vivo strongly suggests that apoptotic molecular steps during cell death generate nuclear autoantigens to sustain the specific autoimmune response in systemic lupus erythematosus.     

The autoimmune accelerating yaa mutation does not accelerate murine AIDS

Murine acquired immunodeficiency syndrome (MAIDS) is characterized by lymphoproliferation, polyclonal B cell activation resulting in the production of autoantibodies, and a progressive immunodeficiency. These are all hallmarks of some autoimmune diseases. Yaa is a Y-chromosome-linked gene that accelerates autoimmune diseases in some autoimmune-prone strains of mice. To further elucidate a possible relationship with autoimmunity, the effect of the Yaa gene on MAIDS was investigated. Analysis of phenotypic and functional disease parameters revealed that Yaa does not accelerate MAIDS disease. This is probably due to the generalized activation of most or all lymphoid cells in MAIDS, which cannot be enhanced by the Yaa gene. This result is in accordance with the selective enhancing effect of the Yaa gene on the immune response against self and foreign antigens in a specific genetic background. It suggests that the autoimmune response associated with MAIDS is a secondary phenomenon. Interestingly, even in wild-type C57BL/6 mice, autoantibody production may contribute overproportionally to the hypergammaglobulinemia associated with MAIDS.     

The role of cytokines in the regulation of ocular autoimmune inflammation

The eye is a unique place for the development of an immune response. Beyond the usual mechanisms of immune restraint, the eye evolved with its exclusive mechanisms such as anterior chamber associated immune deviation. Therefore, immune-mediated inflammation in the eye does not develop at the same pace as in other sites of the body. Here we will address such peculiarities as they regard to ocular autoimmunity, using the experimental autoimmune uveitis as a model to understand the participation of cytokines in the process of aggression against the eye, as well as their immunoregulatory role.     

Recognition of self-peptide-MHC complexes by autoimmune T-cell receptors

T cell receptors (TCR) recognize antigenic peptides displayed by MHC molecules. Whereas T-cell recognition of foreign peptides is essential for immune defense against microbial pathogens, recognition of self-peptides can cause autoimmune disease. Structural studies of anti-foreign TCR showed remarkable similarities in the topology of TCR binding to peptide-MHC, which maximize interactions with the ligand. However, recent structures involving autoimmune and tumor-specific TCR have revealed that they engage self-peptide-MHC with different topologies, which are suboptimal for TCR binding. These differences might reflect the distinct selection pressures exerted on anti-microbial versus autoreactive T cells. The structures also provide new insights into TCR cross-reactivity, which can contribute to autoimmunity by increasing the likelihood of self-peptide-MHC recognition.     

Novel therapeutic strategies based on toll-like receptor signaling

The innate immune system is a critical first line of defense against many microbial, fungal and viral pathogens. Toll-like receptors play a central role in innate immunity, recognizing conserved pathogen-associated molecular patterns and generating signals leading to the initiation of an adaptive immune response. Because of their ability to modulate adaptive immunity, Toll-like receptors represent strategic therapeutic targets for diseases that involve inappropriate adaptive immune responses, such as sepsis, autoimmune disorders, cancer and allergy.     

Regulatory roles for NKT cell ligands in environmentally induced autoimmunity

The development of autoimmune diseases is frequently linked to exposure to environmental factors such as chemicals, drugs, or infections. In the experimental model of metal-induced autoimmunity, administration of subtoxic doses of mercury (a common environmental pollutant) to genetically susceptible mice induces an autoimmune syndrome with rapid anti-nucleolar Ab production and immune system activation. Regulatory components of the innate immune system such as NKT cells and TLRs can also modulate the autoimmune process. We examined the interplay among environmental chemicals and NKT cells in the regulation of autoimmunity. Additionally, we studied NKT and TLR ligands in a tolerance model in which preadministration of a low dose of mercury in the steady state renders animals tolerant to metal-induced autoimmunity. We also studied the effect of Sphingomonas capsulata, a bacterial strain that carries both NKT cell and TLR ligands, on metal-induced autoimmunity. Overall, NKT cell activation by synthetic ligands enhanced the manifestations of metal-induced autoimmunity. Exposure to S. capsulata exacerbated autoimmunity elicited by mercury. Although the synthetic NKT cell ligands that we used are reportedly similar in their ability to activate NKT cells, they displayed pronounced differences when coinjected with environmental agents or TLR ligands. Individual NKT ligands differed in their ability to prevent or break tolerance induced by low-dose mercury treatment. Likewise, different NKT ligands either dramatically potentiated or inhibited the ability of TLR9 agonistic oligonucleotides to disrupt tolerance to mercury. Our data suggest that these differences could be mediated by the modification of cytokine profiles and regulatory T cell numbers.     

Self-tolerance and Autoimmunity in a Regulatory T Cell Model

The class of immunosuppressive lymphocytes known as regulatory T cells (Tregs) has been identified as a key component in preventing autoimmune diseases. Although Tregs have been incorporated previously in mathematical models of autoimmunity, we take a novel approach which emphasizes the importance of professional antigen presenting cells (pAPCs). We examine three possible mechanisms of Treg action (each in isolation) through ordinary differential equation (ODE) models. The immune response against a particular autoantigen is suppressed both by Tregs specific for that antigen and by Tregs of arbitrary specificities, through their action on either maturing or already mature pAPCs or on autoreactive effector T cells. In this deterministic approach, we find that qualitative long-term behaviour is predicted by the basic reproductive ratio R ₀ for each system. When R ₀<1, only the trivial equilibrium exists and is stable; when R ₀>1, this equilibrium loses its stability and a stable non-trivial equilibrium appears. We interpret the absence of self-damaging populations at the trivial equilibrium to imply a state of self-tolerance, and their presence at the non-trivial equilibrium to imply a state of chronic autoimmunity. Irrespective of mechanism, our model predicts that Tregs specific for the autoantigen in question play no role in the system’s qualitative long-term behaviour, but have quantitative effects that could potentially reduce an autoimmune response to sub-clinical levels. Our results also suggest an important role for Tregs of arbitrary specificities in modulating the qualitative outcome. A stochastic treatment of the same model demonstrates that the probability of developing a chronic autoimmune response increases with the initial exposure to self antigen or autoreactive effector T cells. The three different mechanisms we consider, while leading to a number of similar predictions, also exhibit key differences in both transient dynamics (ODE approach) and the probability of chronic autoimmunity (stochastic approach).