ReviewActivation of benign autoimmunity as both tumor and autoimmune disease immunotherapy: A comprehensive review
Section snippets
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 [1].
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 [11], autoimmune diseases arise on a background of a collective of genetic susceptibilities, each contributing relatively low risk [12]; indeed, one's genome does not sentence one irrevocably to an autoimmune disease – even
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 – 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
Pathologic self-reactivity
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 [22]; auto-reactive T cells even fulfill Koch's postulates as etiologic agents of disease [23]; clinically, specific autoantibodies and auto-reactive T cells are the
Autoimmune cancer immunotherapy
In recent years it has become clear that clinically important tumors thrive by inducing the patient's cells in the tumor microenvironment to supply the growing tumor with new blood vessels and growth factors; the tumor also induces Tregs and other endogenous immune cells to suppress the ability of the immune system to attack the tumor (Fig. 1). The clinical benefit of healthy autoimmunity can be inferred by the finding that the administration to cancer patients of antibodies to immune
Anti-tumor autoimmunity to tumor-associated self-antigens
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 [18], [28]; 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
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 (Fig. 4). 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 [29], [30],
HSP60 peptide therapy of type 1 diabetes (T1D)
HSP60 is a homuncular self-antigen; healthy humans are born with autoantibodies that bind HSP60 [18], and cord blood contains a high frequency of HSP60-reactive T cells [40]. 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 [41]. A clone of anti-HSP60 T cells bearing a T-cell receptor sequence shared by different NOD mice [42] identified a peptide segment of HSP60 we termed peptide p277
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
To summarize
The healthy body from birth is outfitted with a shared set of autoimmune reactivities, both innate and adaptive, aimed at a defined set of informative body molecules – the autoimmune homunculus. Fig. 6 summarizes this review. The autoimmune homunculus features, metaphorically like Janus, two functional faces: an aggressive, war-like face that generates effector inflammation; and a benign, peaceful face that generates healing inflammation. Both types of inflammation are needed to maintain and
In honor of Michael Sela and Ruth Arnon
This issue of the Journal of Autoimmunity is dedicated to the honor of Michael Sela and Ruth Arnon. The Journal of Autoimmunity has honored distinguished immunologists as well as published dedicated themes on subjects of critical importance, including, for example, recognition of Abul Abbas, Noel Rose and Ian Mackay, and themes focused on the liver as a victim of autoimmunity [51], [52], [53], [54]. All immunologists and many hundreds of thousands of patients owe thanks and approbation to
References (57)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Host remodeling of the gut microbiome and metabolic changes during pregnancy
Cell
(2012) - et al.
Role of the microbiota in immunity and inflammation
Cell
(2014) - et al.
Innate and adaptive immunity in immune thrombocytopenia
Semin Hematol
(2013) - et al.
The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein
Biochim Biophys Acta
(2014) - et al.
Genome-wide association studies in Sjögren's syndrome: what do the genes tell us about disease pathogenesis?
Autoimmun Rev
(2014) - et al.
A 175 million year history of T cell regulatory molecules reveals widespread selection, with adaptive evolution of disease alleles
Immunity
(2013) Autoantibody repertoires, natural biomarkers and system controllers
Trends Immunol
(2013)- et al.
Autoimmunity can benefit self-maintenance
Immunol Today
(2000) The cognitive paradigm and the immunological homunculus
Immunol Today
(1992)