Paraneoplastic Autoimmune Disorders Research Articles

The Etiology of Paraneoplastic Autoimmunity

Although they may sometimes appear similar, paraneoplastic autoimmunity has a unique pathogenesis, different from the classical autoimmune diseases not associated with cancer. When distinguished clinically, paraneoplastic autoimmunity is more severe and often presents with a broader range of clinical signs and symptoms. Management of these patients is difficult and is usually centered in part on treatment of the underlying malignancy. Self-antigens recognized in the setting of paraneoplastic autoimmunity can be diverse, and the number of determinants recognized within a single antigen can be numerous. This review uses prototypic examples of paraneoplastic immune-mediated diseases and their associated malignancies to describe the mechanisms by which immune dysregulation can occur in the setting of cancer. Specific diseases covered include paraneoplastic pemphigus, Sweet's syndrome, pyoderma gangrenosum, thymoma-associated multiorgan autoimmunity, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, and the paraneoplastic neurological syndromes. The malignancies discussed include thymoma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia, among others. The mechanisms by which cancers induce autoimmunity are broken down into the following categories: disruption of central tolerance, peripheral immune dysregulation, and alteration of self-antigens. For each category, examples of paraneoplastic autoimmune diseases and their associated malignancies are discussed. Finally, mechanisms by which cancer treatment can lead to autoimmunity and examples of polymorphisms that are linked to both cancer and autoimmunity are discussed.

Determination of paraneoplastic autoimmune responses by tumor cell biology and intratumoral IFN-alpha/IL-12 in breast cancer patients.

A wide variety of cancer types has been associated with paraneoplastic autoimmune disorders and with the induction of autoimmunity against several autoantigens, among them self-antigens that are also expressed by tumor cells. This raises the question of autoimmune disorders as a result of immune reactions to the tumor. To date, however, requirements for the generation of autoimmune reactions in cancer patients remain largely unclear. In this study, we characterized conditions in altogether 131 patients, which determine autoimmune responses in primary breast cancer patients. We used ex vivo IFN-γ EliSpot assays against autologous tumor or skin lysates to evaluate tumor- and auto-reactive T-cells (TCs) in the bone marrow (BM) as well as ELISA, ECLIA, and turbidimetric immunoassays for the detection of auto-reactive antibodies in the peripheral blood and compared results to intratumoral cytokine concentrations and pathobiological features of the primary tumor tissue. We here demonstrate a significant correlation between anti-tumor BMTC responses and cellular autoimmune reactivity in primary breast cancer patients (P=0.002). Humoral autoimmune reactions, however, were negatively correlated with anti-tumor TC immunity (P=0.039). We observed auto-reactive BMTCs especially in patients with well-differentiated, hormone receptor-positive carcinomas (P=0.009). Furthermore, elevated concentrations of intratumoral IFN-α significantly correlated with the induction of cellular autoimmune reactivity (P=0.0002), while humoral autoimmune reactions correlated with increased levels of intratumoral IL-12 (P=0.04). Altogether, these data indicate a significant role of the tumor microenvironment and particularly that of IFN-α and IL-12 in the induction of systemic autoimmune responses and imply that the primary tumor tissue represents an integral site of autoimmune regulation in cancer patients.

Thymoma and paraneoplastic myasthenia gravis

Paraneoplastic autoimmune diseases associate occasionally with small cell lung cancers and gynecologic tumors. However, myasthenia gravis (MG) occurs in at least 30% of all patients with thymomas (usually present at MG diagnosis). These epithelial neoplasms almost always have numerous admixed maturing polyclonal T cells (thymocytes). This thymopoiesis—and export of mature CD4+T cells—particularly associates with MG, though there are rare/puzzling exceptions in apparently pure epithelial WHO type A thymomas. Other features potentially leading to inefficient self-tolerance induction include defective epithelial expression of the autoimmune regulator (AIRE) gene and/or of major histocompatibility complex class II molecules in thymomas, absence of myoid cells, failure to generate FOXP3+ regulatory T cells, and genetic polymorphisms affecting T-cell signaling. However, the strong focus on MG/neuromuscular targets remains unexplained and suggests some biased autoantigen expression, T-cell selection, or autoimmunization within thymomas. There must be further clues in the intriguing serological and cellular parallels in some patients with late-onset MG but without thymomas—and in others with AIRE mutations—and in the contrasts with early-onset MG, as discussed here.

Thymoma accompanied by lichen planus

Thymomas are associated at a high frequency with paraneoplastic autoimmune diseases. We treated a 64-year-old male with a thymoma, who also had lichen planus. The tumor was resected and diagnosed as thymoma, however, the symptoms associated with lichen planus did not subside and persisted. A preoperative examination showed an elevated serum level of squamous cell carcinoma antigen, which gradually decreased to normal after surgery. The findings of this case are interesting for understanding the correlation between a thymoma and autoimmune abnormalities.

Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome

Paraneoplastic autoimmune disorders are usually regarded as syndromic (for example, paraneoplastic optic neuropathy with CRMP5 antibody, opsoclonus with ANNA-2 (antiRI) antibodies. However, for most paraneoplastic antibodies, the spectrum of clinical manifestations is broader than what was initially described in syndromic patients. This study evaluated coexisting autoantibodies in sera of 553 patients with a neurological presentation and one or more paraneoplastic neuronal nuclear or cytoplasmic autoantibodies: antineuronal nuclear autoantibody type 1 (ANNA-1), ANNA-2, ANNA-3; Purkinje cell cytoplasmic autoantibody type 1 (PCA-1), PCA-2; and CRMP-5-immunoglobulin G or amphiphysin-immunoglobulin G. Except for PCA-1, which occurred alone, 31% of sera had more than one of these autoantibodies. In addition, 25% of sera had neuronal calcium channel (P/Q-type or N-type), potassium channel, ganglionic acetylcholine receptor, muscle acetylcholine receptor, or striational antibodies. The authors conclude that the autoantibody profiles observed in patients with paraneoplastic disorders imply the targeting of multiple onconeural antigens and predict the patient’s neoplasm, but not a specific neurological syndrome. They emphasize that optimal serological evaluation for the detection of autoantibody profiles predictive of cancer requires broad screening for autoantibodies. Indeed, diagnostically important autoantibodies are often missed if a single or limited number of individual antibodies are tested.—Valérie Biousse

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease

Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA+CD8+ T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8+ phenotype. Moreover, it is primarily the proportion of circulating CD45RA+CD8+ T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma.

Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease

AbstractThymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA+CD8+ T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8+ phenotype. Moreover, it is primarily the proportion of circulating CD45RA+CD8+ T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma.

Thymoma.

Thymomas are fascinating tumors because of their multifaceted clinical presentation, including an unrivaled frequency of associated paraneoplastic autoimmune diseases and an astounding histologic heterogeneity. Thus, thymomas challenge the clinician, pathologist, and immunologist alike with complex diagnostic and therapeutic problems in almost all fields of medicine, radiology, nuclear medicine, surgery, radiooncology, and pathology. This review highlights recent progress in these fields, including the new World Health Organization's classification of thymomas, and reports on the beginning discovery of the genetic basis of thymoma oncogenesis and the cellular and molecular immunopathology of thymoma-associated paraneoplastic autoimmunity.

Lambert-Eaton syndrome antibodies: reaction with membranes from a small cell lung cancer xenograft

Lambert-Eaton myasthenic syndrome (LEMS) is a paraneoplastic autoimmune disorder caused by an IgG-mediated reduction in number of presynaptic voltage-gated calcium channels (VGCC) at the neuromuscular junction. In at least 50% of cases, the stimulus for antibody production may be VGCC on small cell lung cancer (SCLC). In this study membranes isolated from a human small cell lung cancer xenograft (Mar), that bound [ 3H]PN200-110, a VGCC antagonist, were subjected to Western blotting using plasma from 12 LEMS patients and eight controls. Although one band recognised by 3 12 LEMS IgGs might be associated with the VGCC, a number of other proteins were recognised both by LEMS plasma, and by plasma from patients with other disorders. The results illustrate the difficulties found using Western blotting with autoimmune plasma to identify specific polypeptides in a crude antigen preparation.