Paraneoplastic Immune-Mediated Disorders

Immune-mediated paraneoplastic neurologic disease (PND) occurs as a consequence of the body’s immune response to a neoplasm. This is a complex interaction evolving during tumor development, varying with tumor type, organ involvement, and the individual, per se. Autoimmunity, or organ-specific immune-mediated injury, is a consequence of loss of immune tolerance. Active primary immune responses combined with dysregulation of normal immune activation checkpoints, varying by organ system and certain individually inherent factors, provides the setting for specific immunologic-based injuries.

Autoantibody detection provides important markers to identify various PNDs. In the context of cancer, these are either consequences of specific tumor immune responses or less specific markers of autoimmunity subsequent to immune checkpoint dysregulation. An evolving spectrum of PND autoantibodies is increasingly recognized, associated with a broad spectrum of nervous system disorders. Thus their presence serves primarily as a predictor of an underlying neoplasm rather than a specific neurologic syndrome.

These PND autoantibodies, available for clinical measurement, most likely represent a subset of those generated by the body’s immune response to the neoplasm. With respect to the associated neurologic autoimmunity, the antibodies may or may not represent actual mediators of tissue injury. When these antibodies are the mediators of neurologic disease, it is fortunate that they not only serve as specific markers for that disorder, but they can become therapeutic targets. Unfortunately, autoantibodies are often not either necessary or sufficient to express neurologic injury. Typically, neurologic lesions result from complex expressions of activated cellular elements, cytokines, and antibodies in concert with specific patterns of immune dysregulation and loss of tolerance.

This immune response, occurring throughout the neoplasm’s life cycle, can be conceptualized as immunoediting (Schreiber 2011). A neoplasm likely arises through a complex set of germline variations, tissue-specific genetic mutation, and environmental interactions, resulting in a process of tissue transformation. Senescence, apoptosis, and innate and adaptive immune response elements may combine to restore that tissue to health, eventually eliminating the neoplasm. Alternatively, the neoplastic transformation continues to evolve, potentiating inherently immunogenic processes and an array of immune response elements that may successfully eliminate the neoplasm or successfully suppress it.

Clinically, such neoplasms may be undetectable, occult, or detectable, yet at limited early-stage disease causing no or very limited tissue-specific symptoms. Therefore some neoplasms exist in an undefined equilibrium with an immune response, failing to progress without any clinical effort (surgery, radiotherapy, chemotherapy) to suppress or remove it. Unfortunately, a neoplasm frequently continues on a path of genetic and epigenetic mutation and modification. Once it becomes less immunogenic, changing its relationship with the tissue microenvironment, it eventually becomes locally immunosuppressed. Once the tumor escapes immune control, it can then progress.

As a neoplasm evolves from potential elimination to an immunoequilibrium, and eventually to escape, immune responses to tumor-specific antigens are activated. These antigens represent unique cell surface components of the tumor, or intracellular components exposed to the local environment after apoptosis occurring in its natural evolution. Local tissue macrophages process these antigens, presenting them to cytotoxic T cells or to tissue dendritic cells migrating to regional lymph nodes, thereby activating T and B lymphocytes. The pattern of immune activation toward Th1, Th2, Th17, and T regulatory cells (Tregs), governed by the cytokine milieu, dictates the effects of the immune response.

The autoimmune expression within this immunoediting context of cancer is further regulated by multiple immune checkpoints. These include but are not limited to the status of regional and systemic Tregs, Th17 mediators, regulatory B cells (B10 via interleukin-10 [IL-10]), relative activation of STAT 4 versus STAT 6 tran-scription factors, genetic and epigenetic variation regulating any given individual’s immune response and generation of tolerance, the status of important negative regulators of immune activation such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed cell death 1 (PD-1) and its ligand B7-H1 (or PD-L1). For example, blockade of CTLA-4 leads to development of autoimmunity within several organ systems. The expression of autoimmunity within the nervous system also relates to a host of additional factors, including regulation of immune effector access across the blood-brain barrier or blood–peripheral nerve barrier, as well as mechanisms of antigen presentation within the nervous system.

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