The nature of inflammation and autoimmune disease An autoimmune disease can be defined as a clinically distinct illness caused by an immune reaction to an otherwise normal molecule or tissue component of the subject’s body. The damage inflicted by most autoimmune diseases is marked by recurrent or chronic forms of noxious inflammation; so autoimmune disease is linked to the regulation of inflammation; the link makes sense because the immune system, in its combined innate and acquired arms, is the orchestrator and manager of inflammation.
Inflammation has been defined as a process that is initiated by some injury and proceeds towards healing. Inflammation, in essence, arises from an interaction e better, a two-way dialog e between the immune system and the body in its care.
Inflammation is a complex and dynamic process that makes it possible for the multicellular, differentiated organism to repair the blows, insults and infections that visit the body as an inevitable condition of post-developmental life; inflammation, like pre-natal development itself, involves modifications in vascular and connective tissues, the flows of blood and extra-cellular and intra-cellular fluids, programed cell death along with cell proliferation, cell migrations, metabolic adjustments, shifting concentrations and flows of signal molecules and cellular dedifferentiation and differentiation. From this point of view, we can understand how tumors can enhance their growth by stimulating a chronic inflammatory response at the site.
The task of managing inflammation is exceedingly complicated because the immune system is also engaged in an ongoing dialog with the symbiotic microbiome and viral inhabitants of the healthy body. Symbiosis complicates the distinction between self and nonself; our symbiotic partners are encoded by DNA that is foreign to our genome, yet our healthy bodies are populated with more prokaryote cells than they are with eukaryote, mammalian cells.
The causes of autoimmune disease
What are the inciting causes of immune mismanagement leading to autoimmune diseases? Causality in biology can usually be parsed into genes or environment, or to a combination of the two. Except for a few, relatively rare conditions such as APS-1 due to the AIRE mutation, autoimmune diseases arise on a background of a collective of genetic susceptibilities, each contributing relatively low risk; indeed, one’s genome does not sentence one irrevocably to an autoimmune disease e even monozygotic twins are often discordant for developing an autoimmune diseas.
The vast majority of people who harbor autoimmune disease susceptibility genes will never develop the clinical disease e in fact, autoimmune-disease susceptibility alleles are quite prevalent and some of these alleles appear to be advantageous in fighting infections. Thus, the environment would have to be a major factor, if not the major factor in the induction of autoimmune disease; if so, what aspect of the environment is to blame? The simplest answer would be to say that an autoimmune disease arising in different people is likely to arise through different inciting factors in each patient; indeed, any factor that activates inflammation (or immune activation) could lead to an autoimmune disease, whenever immune regulation of the inflammatory response fails to manage the situation appropriately.
Physiological self-reactivity and the immunological homunculus
The tri-partite dialog of the immune system with our body and with our symbiotic residents requires the transmission and reception of signals between the participants: dialogs depend on understandable languages e be they molecular or verbal. It is clear that signaling by way of cytokines, chemokines, and toll-like and other innate receptors and their ligands form regulatory networks between the immune system, the body and the microbiome.
In addition to these communication networks based on innate signals, I have proposed that the autoantibodies and auto-reactive B cells and T cells that are demonstrable in healthy immune repertoires also participate in the ongoing immune-body dialog; benign autoimmunity, by sensing key biomarker antigens expressed by the tissues, can help manage healing inflammation. These autoreactive repertoires, in effect, form a picture of informative body molecules that can help disclose the state of the body to the immune system e fine-tuning the inflammatory process is enhanced by reliable self-antigen signaling.
The immunological homunculus theory proposes that healthy autoimmune repertoires contribute to healthy immune management of inflammation. Autoantibodies have been noted to enhance wound healing and auto-reactive T cells have been reported to exert a protective function in the central nervous system.
In contrast to the possible contribution of benign autoimmunity to health, the pathogenic roles of autoimmune reactions in autoimmune disease are uncontestable; my colleagues and I were among the first to demonstrate that a single clone of activated, auto-reactive T cells could mediate an experimental autoimmune disease in rodents; auto-reactive T cells even fulfill Koch’s postulates as etiologic agents of disease; clinically, specific autoantibodies and auto-reactive T cells are the hallmarks of human autoimmune diseases. The problem is to resolve the paradox of benign autoimmunity as a component of a healthy immune system and pernicious autoimmunity as agents of autoimmune disease.
The observation that identical target antigens have been identified in both types of autoimmunity suggests that autoimmune disease involves a transition from benign autoimmunity to pernicious autoimmunity; conversely, one could imagine that a pernicious autoimmune disease might be reversed by inducing a transition from pernicious autoimmunity back to benign autoimmunity. I shall provide two examples below.
Anti-tumor autoimmunity to tumor-associated selfantigens
Autoimmunity to tumor-associated molecules is expressed in healthy humans from the time of birth: we have found that many of the most prevalent and abundant autoantibodies in the benign auto-reactive repertoires present in healthy newborns and their mothers bind to known tumor-associated self-antigens; thus neonates, who are likely to be born free of tumors, already express tumor-associated autoimmunity in preparation, as it were, for neoplastic accidents. The immune system of the developing fetus is exposed to differentiation molecules that become downregulated as development progresses; but later in life these molecules can become over-expressed by dedifferentiating tumor cells.
Thus, one may speculate that prenatal exposure to differentiation molecules may prime the human for tumor-associated immune reactivity that can be induced to attack potential tumors when neoplastic dedifferentiation does occur later in life. The idea is that such potential tumor-associated autoimmune reactivity is encoded in the healthy immunological homunculus. We do not as yet know whether latent anti-tumor homuncular autoimmunity (both T cell and B cell) is essential to effective anti-PD1 or antiCTLR4 antibody therapy, but this is not an unreasonable working hypothesis.
T-cell vaccination (TCV)
TCV is a type of autologous, personalized cell-based therapy in which a sample of a subject’s autoimmune T cells are expanded and activated ex vivo; aliquots of the activated T cells are then attenuated by irradiation and injected subcutaneously back into the subject as a therapeutic vaccine. The subject responds to his or her own vaccine T cells by activating regulatory networks of T cells that, in turn, arrest the damaging inflammation that causes the autoimmune disease.
Note that the regulatory T cells induced by TCV are essentially autoimmune in that they recognize epitopes in the disease-causing T-cell receptors e an example is anti-idiotypic autoimmune regulation. Other self-antigen targets presented to T-regulators by activated effector T cells have been identified as “ergotopes” e biomarkers of the state of activation of the disease-causing T cells. Thus, TCV can be considered metaphorically to enlist healthy autoimmunity to fight pernicious autoimmunity.
HSP60 peptide therapy of type 1 diabetes (T1D)
HSP60 is a homuncular self-antigen; healthy humans are born with autoantibodies that bind HSP60, and cord blood contains a high frequency of HSP60-reactive T cells. We found that the onset of type 1 diabetes (T1D) in both NOD mice and in humans is associated with up-regulation of anti-HSP60 autoantibodies and T cells. A clone of anti-HSP60 T cells bearing a T-cell receptor sequence shared by different NOD mice identified a peptide segment of HSP60 we termed peptide p277 (positions 437e460 in the HSP60 human sequence); subcutaneous administration of a single dose of 100 mg of p277 arrested the destruction of pancreatic beta cells, even in mice that were already clinically diabetic.
The finding that humans with new onset T1D also manifested autoimmune responses to HSP60 and p277 prompted us to explore the possible clinical usefulness of p277 peptide therapy; the peptide was slightly modified to enhance stability and was administered subcutaneously in an emulsion of a digestible lipid vehicleethe combination of p277 and vehicle is termed DiaPep277.
Treating autoimmune disease: to suppress or to activate?
At the present time, clinical therapy for autoimmune diseases is dominated by the use of powerful agents, chemical or biological, that suppress the immune system globally. Such suppressive treatments are costly in undesirable side effects and are not effective in many patients.
It is true that artificially suppressing the immune system can arrest the noxious inflammation that causes the disease, but global suppression of the immune system over time is likely to neutralize the possibility of reinstating healthy immune regulation; the suppressed subject gets hooked on continuous suppression. The use of benign autoimmune agents such as TCV and selfpeptides contrast greatly with blanket immune suppression; in this case, we don’t suppress the immune system globally, rather we attempt to stimulate endogenous immune regulatory mechanisms and thereby enlist the immune system to manage the inflammatory reaction properl .
Author: Irun R. Cohen