Aetiology and pathogenesis of paraneoplastic autoimmune disorders

Journal Pre-proof Aetiology and pathogenesis of paraneoplastic autoimmune disorders

Guojun Geng, Xiuyi Yu, Jie Jiang, Xinhua Yu PII:

S1568-9972(19)30232-0

DOI:

https://doi.org/10.1016/j.autrev.2019.102422

Reference:

AUTREV 102422

To appear in:

Autoimmunity Reviews

Received date:

16 June 2019

Accepted date:

21 June 2019

Please cite this article as: G. Geng, X. Yu, J. Jiang, et al., Aetiology and pathogenesis of paraneoplastic autoimmune disorders, Autoimmunity Reviews(2019), https://doi.org/ 10.1016/j.autrev.2019.102422

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Journal Pre-proof Aetiology and pathogenesis of paraneoplastic autoimmune disorders Guojun Geng1*, Xiuyi Yu1* , Jie Jiang1§ and Xinhua Yu1,2§ 1

Department of Thoracic Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of

Xiamen University, Xiamen, People's Republic of China. 2

Priority Area Asthma & Allergy, Research Center Borstel, 23845 Borstel, Germany, Airway

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Research Center North (ARCN), Member of the German Center for Lung Reaspsearch (DZL)

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Correspondence should be addressed to

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§

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* Contributed equally

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Jie Jiang

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Department of Thoracic Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of

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Xiamen University, Xiamen, People's Republic of China Email: [email protected] and Xinhua Yu

Priority Area Asthma & Allergy, Research Center Borstel, 23845 Borstel, Germany, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL) Email: [email protected]

Journal Pre-proof Abstract: Paraneoplastic autoimmune disorders (PAD) represent a group of autoimmune diseases associated with neoplasms. As a consequence of a remote autoimmunity-mediated effect, PAD are found in multiple organs or tissues, including the skin, blood and nervous system. Compared with non-paraneoplastic autoimmune diseases, PAD have different aetiologies, pathologies, disease symptoms and treatment responses. There are two main origins of

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autoimmunity in PAD: neoplasm-mediated dysregulated homeostasis in immune cells/organs

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and in autoantigens. Pathologically, PAD are mediated predominantly by either

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autoantibodies or autoreactive T-cells. In the past decade, significant progress has been

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achieved in increasing our understanding of the aetiology and pathology of PAD. In this review article, we aim to provide a comprehensive overview of the recent advances in this

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field.

Journal Pre-proof 1

Introduction

Autoimmune diseases are mediated by immune reactions to self-components of organisms 1. Under physiological conditions, autoimmune attacks are elegantly and sophistically controlled via processes termed self-immune tolerance. Self-immune tolerance is established at two levels: during the development of lymphocytes (central tolerance)

2

and during interactions

between mature lymphocytes and autoantigens (peripheral tolerance) 3. However, under

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certain conditions, self-immune tolerance can be breached, resulting in autoimmunity and

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autoimmune disorders 4. Many factors are able to trigger autoimmunity and autoimmune

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diseases, and neoplasms are one of them. Neoplasms represent a type of abnormal and excessive tissue or cell growth and can have a benign (benign tumour) or malignant (cancer)

e-

form 5. During the development of neoplasms, neoantigens are generated because of

6;7

.

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autoimmunity

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mutations or abnormal gene expression, and such neoantigens are able to provoke

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Interestingly, epidemiological studies have demonstrated that autoimmune disorders are positively associated with cancer, and cancer is associated with a high risk of autoimmune 8

and vice versa

9;10

. The associations between cancer and autoimmune diseases

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diseases

might have many underlying reasons, including common risk factors, e.g., smoking, common genetic basis, side-effects of medication usage, and frequent clinical evaluations

11;12

. In

addition, the associations between cancer and autoimmune diseases could also result from cancer-mediated autoimmunity, and paraneoplastic autoimmune disorders (PAD) are a good example of this type 13;14. PAD are a group of autoimmune diseases associated with neoplasms, mainly cancer. Principally, the symptoms of those disorders are not a direct consequence of malignancies but instead result from neoplasm-triggered autoimmunity

14;15

. In recent decades, there has been

Journal Pre-proof considerable improvement in our understanding of PAD

16

. In this review article, we

summarize recent progress in this field and discuss the aetiology and pathology of PAD.

2 Paraneoplastic autoimmune disorders As a consequence of the remote autoimmunity-mediated effects of neoplasms, PAD are found

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in multiple organs and tissues, such as the skin, blood and nervous system (Table 1).

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2.1 Paraneoplastic autoimmune cutaneous manifestations

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The skin is a main target of paraneoplastic autoimmune attack. The manifestations of PAD

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can be present in the skin with or without affecting other organs, leading to the development

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of multiple diseases or syndromes.

autoimmune

multiorgan

syndrome

(PAMS),

previously

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Paraneoplastic

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2.1.1 Paraneoplastic autoimmune multiorgan syndrome

paraneoplastic pemphigus, was first described in 1990 by Anhalt and colleagues

known 17

as

. Several

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malignancy or lymphoproliferative disorders have been associated with PAMS, including thymoma, lymphoma and chronic lymphocytic leukaemia (CLL)

17;18

. Unlike classical

pemphigus, which features autoantibodies directed against only desmogleins, PAMS are characterized by the presence of autoantibodies against a wide range of proteins that are functionally involved in the regulation of skin integrity; these include desmogleins, plakins, cadherins, alpha-2-macroglobulin such as 1 (A2ML1), and bullous pemphigoid antigen 180 kD (BP180) and BP230 19. The differences in autoantibodies between PAMS and classical pemphigus suggest a distinct origin of autoimmunity and also lead to different clinical symptoms. On the one hand, in addition to suprabasal acantholysis, which is the only cutaneous symptom of classical

Journal Pre-proof pemphigus, other skin involvement is often observed in PAMS, including subepdermal blistering and keratinocyte necrosis

20

. On the other hand, extracutaneous manifestations are

common in PAMS but not classical pemphigus and include ocular complications, muscle weakness, and complications in the respiratory system and gastrointestinal tract 19. 2.1.2 Cancer-associated systemic sclerosis Systemic sclerosis (SSc) is a rheumatoid disease characterized by autoimmunity, vasculopathy

f

and fibrosis 21. According to the status of skin involvement, cases of SSc can be classified into

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two groups: limited cutaneous SSc (lcSSc), in which patients have skin manifestations only in

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the distal extremities with or without face and upper neck involvement, and diffuse cutaneous SSc (dcSSc), in which skin manifestations extend from the distal extremities to the proximal

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limbs and trunk 21. In addition to the skin, many other organs are often affected in SSc, such

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as the lungs, kidneys and the gastrointestinal tract

21

.

Epidemiological studies have shown that there are more cases of cancer among patients with

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anti-RNA polymerase III (anti-RNAP) antibodies than in those with other autoantibodies 22;23,

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suggesting a paraneoplastic phenomenon in this subset of SSc. This notion was verified by a

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study published in 2014, in which Joseph et al. demonstrated that the genetic mutation of genes encoding RNAP within cancer cells triggered cross-reactive humoural autoimmune responses against the protein

24

. With regard for malignancies associated with SSc, the most

common subtype is breast cancer, which is followed by haematological, gastrointestinal and gynaecological cancers 22. 2.1.3 Thymoma-associated multiorgan autoimmunity Thymoma-associated multiorgan autoimmunity (TAMA) is a graft-versus-host-like disease (GVHLD) that affects multiple organs, including the skin 25. This disorder was reported in the 1990s in two studies that showed that malignant thymoma is associated with GVHLD that affects the intestine and skin26;27. In the intestine, the manifestations of TAMA appear as an

Journal Pre-proof unusual form of colitis characterized by minimal inflammation but prominent apoptotic lesions within the crypt epithelium27. The skin manifestations of TAMA present as erythrodema, which is characterized by interface and perivascular dermatitis with necrotic keratinocytes 28. In addition to the skin and intestine, the liver is often targeted by TAMA28. To date, no autoantibodies have been found to be associated with TAMA. Because graftversus-host disease is a T cell-mediated disorder 29, it is conceivable that TAMA is mediated

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by autoreactive T cells.

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Apart from the abovementioned diseases, two other syndromes, Sweet syndrome and

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Pyoderma gangrenosum, are also paraneoplastic cutaneous disorders. Both of these syndromes clinically feature neutrophilic dermatosis

30;31

. Immunologically, they are

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characterized by the increased expression of proinflammatory cytokines and sterile

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inflammation in the absence of autoreactive T cells and autoantibodies 32;33. Therefore, Sweet

autoimmune diseases.

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syndrome and Pyoderma gangrenosum are more likely to be auto-inflammatory disorders than

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2.2 Paraneoplastic autoimmune haematologic manifestations

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Paraneoplastic autoimmunity can also cause complications in the haematologic system, resulting in autoimmune cytopaenias such as autoimmune haemolytic anaemia, immune thrombocytopenia, and pure red cell aplasia. 2.2.1 Paraneoplastic autoimmune haemolytic anaemia Paraneoplastic autoimmune haemolytic anaemia (AIHA) is mediated by autoantibodies against the membrane antigens on red blood cells. These autoantibodies, which include "warm" IgG autoantibodies and "cold" IgM autoantibodies 34, are capable of causing the death of red blood cells, leading to haemolytic anaemia. The main malignancies associated with paraneoplastic AIHA are lymphoproliferative disorders, such as CLL and lymphoma

35;36

. In

Journal Pre-proof addition, a small number of patients with paraneoplastic AIHA are associated with solid tumours, including renal cell cancer and Kaposi sarcoma 37. 2.2.2 Paraneoplastic pure red cell aplasia Another paraneoplastic autoimmune disorder characterized by anaemia is pure red cell aplasia (PRCA)

38

. Unlike AHIA, in which anaemia results from the autoantibody-mediated

destruction of red blood cells, paraneoplastic PRCA is mediated by autoantibodies that

38

. In 1996, Casadevall and colleagues identified anti-

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or an absence of erythroid precursors

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interrupt erythroid differentiation. As a consequence, patients with PRCA show a reduction in

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erythropoietin antibodies as pathogenic autoantibodies in PRCA

39

. Mechanistically,

autoantibodies against erythropoietin prevent the binding of erythropoietin to its receptor and

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thereby block the differentiation of erythroid progenitors

39

. CLL and thymoma are major

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malignancies that present in paraneoplastic PRCA 36;38;39.

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2.2.2 Paraneoplastic autoimmune thrombocytopenia Autoimmune thrombocytopenia (AITP) is a rare autoimmune disease caused by abnormal 40;41

. Based on the absence or presence of associated diseases,

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autoimmunity against platelets

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AITP can be classified as either primary or secondary 41. When secondary AITP is associated with malignancies, it is called paraneoplastic AITP 36. Many cancers have been demonstrated to be associated with AITP; these include both lymphoproliferative disorders, such as CLL, as well as lymphoma and solid tumours, such as lung and breast cancer 42;43. 2.3 Paraneoplastic autoimmune manifestations in the peripheral nervous system 2.3.1 Thymoma-associated myasthenia gravis Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies against the different components of neuromuscular junctions

44

. The binding of those autoantibodies to

target autoantigens interferes with neuromuscular transmission, leading to muscle weakness and fatigue

45

. A strong association has been demonstrated between MG and thymoma, with

Journal Pre-proof approximately 30% of patients with thymoma developing MG and 10-20% of patients with MG carrying thymoma 45. Interestingly, although several pathogenic autoantibodies, such as those against acetylcholine receptor (AChR), muscle-specific kinase (MUSK) and lipoprotein-related protein 4 (LRP4), are associated with MG, thymoma-associated MG is exclusively characterized by the presence of autoantibodies against AChR

44;46

. In addition, thymothymectomy surgery substantially 46

, suggesting that the thymoma is the origin of

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decreased the titres of anti-AChR antibodies

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autoimmunity against AChR.

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2.3.2 Cancer-associated Lambert-Eaton myasthenic syndrome Lambert-Eaton myasthenic syndrome (LEMS) is another autoimmune neuromuscular junction

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disorder characterized by fatigable muscle weakness 47. The pathology of LEMS is related to

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the autoantibody-mediated loss of functional P/Q-type voltage-gated calcium channels (VGCCs) on presynaptic nerve terminals 47. These P/Q-type VGCCs, which are composed of

. Autoantibodies against the P/Q-type VGCCs isolated from the sera of patients have been

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48

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multiple subunits, are involved primarily in acetylcholine release from motor nerve terminals

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shown to target multiple subunits of the channels 49. LMES is a rare autoimmune disease with a crude prevalence of 9.2 per million

50

.

Approximately 60% of LMES cases occur as a paraneoplastic disorder, most commonly in association with small cell lung cancer (SCLC)

51

. In a prospective study, among 63 patients

with SCLC, 5 (8%) were positive for autoantibodies against VGCC, and 2 (3%) had LEMS 52. 2.3.3 Paraneoplastic peripheral nerve hyperexcitability syndromes Autoantibodies targeting neuromuscular junctions can also lead to undulating myokymia or neuromyotonia, which is exemplified by anti-voltage-gated potassium channel (VGKC) antibodies in peripheral nerve hyperexcitability syndromes (PNHS)

53

. By binding to their

targets, those autoantibodies can decrease the number of membrane-bound VGKCs and

Journal Pre-proof thereby increase the release of the neurotransmitter

53;54

. PNHS can also be paraneoplastic, in

which it is commonly associated with SCLC and thymoma 55. 2.3.4 Paraneoplastic autoimmune retinopathy Another paraneoplastic autoimmune manifestation observed in the peripheral nervous system is autoimmune retinopathy (AR), a rare autoimmune disease characterized by vision loss, scotomas, visual field deficits and photoreceptor dysfunction56. It is believed that the presence

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of circulating autoantibodies against retinal antigens is responsible for the photoreceptor

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damage and consequent symptoms observed in these cases56. Based on its association with

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tumours, AR can be categorized into two groups: paraneoplastic and non-paraneoplastic, with paraneoplastic AR further subdivided into cancer-associated AR and melanoma-associated AR . Several autoantibodies have been suggested to be associated with paraneoplastic AR

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56

58

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these include the anti-recoverin and anti-enolase antibodies

57

;

. Interestingly, autoantibodies

against recoverin are almost exclusively present in the sera of patients with paraneoplastic

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AR, while anti-enolase antibodies are nearly equally likely to be found in the sera of patients

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with paraneoplastic and non-paraneoplastic AR

59

. Previous studies have demonstrated that

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autoantibodies against both recoverin and enolase are able to induce the apoptosis of retinal cells, suggesting that they are pathogenic in the development of AR 60;61. 2.4 Paraneoplastic autoimmune manifestations in the central nervous system 2.4.1 Paraneoplastic cerebellar degeneration Paraneoplastic cerebellar degeneration (PCD) presents as a heterogeneous group of malignancy-associated

autoimmune

neuroimmunological

disorders

featured

by

subacute cerebellar ataxia, dysarthria and intention tremor 62. Immunologically, PCD is characterized by autoantibodies against antigens present on cerebellar Purkinje cells, including both intracellular and membrane-bound proteins62;63. PCD presenting with different autoantibodies have different pathogeneses and are associated with malignancies. For

Journal Pre-proof example, PCD associated with autoantibodies against an intracellular antigen, Yo (cerebellar degeneration-related

protein

gynaecological maligancies

2),

is

often

associated

with

breast

and

63;64

, and its pathogenesis is believed to be mediated

predominantly by autoreactive CD8+ T cells rather than autoantibodies

65

. Conversely, PCD

associated with a membrane-bound antigen, Tr (delta/notch-like epidermal growth factorrelated receptor (DNER)), is mainly associated with Hodgkin's lymphoma

66

, and it is

conceivable that the binding of these autoantibodies to DNER contributes to disease

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development 67.

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2.4.2 Paraneoplastic autoimmune encephalitis

Autoimmune encephalitis (AE) is a group of autoimmune disorders that occur the central

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nervous system (CNS) and are mediated by autoantibodies against neuronal cell-surface or

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synaptic receptors, including N-methyl-D-aspartate receptor (NMDAR), leucine-rich gliomainactivated protein 1 (LGI1), gamma-amino-butyric acid type A receptor (GABA(A)R),

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GABA(B)R, and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) 68;69

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. The binding of those autoantibodies interferes with the function of neuronal cell-surface

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or synaptic receptors, leading to the dysfunction of neuronal cells and consequent neuropsychiatric syndromes, such as memory loss, seizures, psychiatric symptoms, abnormal movements, and hypoventilation 70. AE can occur in the presence or absence of malignancies, with the former called paraneoplastic AE

68

. AE can be divided into several subgroups

according to the associated autoantibodies, and those subgroups differ from each other in terms of their associations with malignancies, genetics, symptoms, epidemiology, and pathogenesis

70

. For example, among the two most common AE subgroups, up to 50% of

cases of anti-NMDAR AE are associated with malignancies, predominantly teratoma

71;72

,

while only approximately 10% of patients with anti-LGL1 AE have cancer, predominantly thymoma

68;73

. Genetically, anti-NMDAR AE is associated with HLA_DRB1*1602

anti-LGI1 AE is strongly associated with HLA_DRB1*07:01

75

74

, while

. Although the prevalences of

Journal Pre-proof these two subgroups are comparable, patients with anti-NMDAR AE are usually younger, while anti-LGI1 AE often affects older people

68

. With regard for symptoms, although both

subgroups share some symptoms, faciobrachial dystonic seizures and hyponatremia are more often observed in anti-LGI1 AE, while dyskinesia and autonomic instability are more often observed in anti-NMDAR AE 68;75. 2.4.3 Paraneoplastic encephalomyelitis

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Paraneoplastic encephalomyelitis (PEM) is a multifocal autoimmune disorder of the CNS

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associated with remote malignancies 76. The diagnosis of PEM is considered when at least two

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of the following are involved: limb encephalitis, PCD, rhomboencephalitis, sensory neuronopathy, myelitis and the csympathetic and parasympathetic ganglia and nerves

76

.

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Approximately 60% of cases of PEM are associated with autoantibodies against the Hu

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antigen (also named type 1 antineuronal nuclear antibody (ANNA1)) patients with anti-Hu-associated PEM

also

have SCLC

77;78

77;78

.

, and the majority of The predominant

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neurological syndromes observed in anti-Hu-associated PEM are sensory neuropathy,

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cerebellar ataxia, limbic encephalitis and multifocal involvement

78

.. Because Hu is an

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intracellular antigen, anti-Hu-associated PEM is believed to be mainly mediated by autoreactive T cells

79

. In addition to anti-Hu antibodies, several other autoantibodies have

also been suggested to be associated with PEM; these include anti-Ma and anti-collapsin response mediator protein 5 (CRMP5) antibodies 80;81 . 2.4.4 Paraneoplastic opsoclonus-myoclonus-ataxia syndrome Opsoclonus-myoclonus-ataxia syndrome (OMS) is a severe autoimmune CNS disorder that causes lifelong neurological disability

82

. Unlike most other paraneoplastic autoimmune

disorders, paraneoplastic OMS predominantly affects young children; its symptoms include opsoclonus, myoclonus and ataxia82;83. Approximately 50% of patients with OMS are associated with neuroblastoma, and some adult patients with OMS have breast cancer or

Journal Pre-proof SCLC

82;83

. One autoantigen identified in paraneoplastic OMS is neuro-oncological ventral

antigen 1 (NOVA1), a protein expressed in both neurons and tumours

84

. NOVA1 is an

intracellular RNA-binding protein that has been implicated in neurological diseases and cancers 85. 2.4.5 Paraneoplastic stiff-person syndrome Stiff-person syndrome (SPS) is a rare autoimmune disorder of the CNS characterized by 86

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progressive rigidity and muscle spasms affecting the axial and limb muscles

. Among 87

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patients ith SPS, less than 10% also have malignancies (the paraneoplastic variant)

.

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Although both anti-glutamic acid decarboxylase (GAD)65 and anti-amphiphysin antibodies are associated with SPS, paraneoplastic SPS is almost exclusively associated with 87;88

. In addition, most patients with paraneoplastic SPS

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autoantibodies against amphiphysin

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are female, and the main malignancy associated with SPS is breast cancer

87

. Amphiphysin

is a synaptic vesicle protein that plays an essential role in the process of depolarization-

rn

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induced exocytosis of neurotransmitters 89.

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3 Aetiology and pathology of paraneoplastic autoimmune disorders 3.1 Origin of autoimmunity in paraneoplastic autoimmune disorders Autoimmunity results from a break in immune tolerance to self-antigens and can be caused by dysregulated homeostasis of the immune system, autoantigens, or target tissues

90

. In PAD,

autoimmunity can result from neoplasm-mediated dysregulated homeostasis of the immune system or autoantigens. In addition, the treatment of PAD is another source of autoimmunity. 3.1.1 Neoplasm-mediated dysregulation in the immune system The immune system contains two compartments, a central immune system (CIS), in which lymphocytes are generated, and a peripheral immune system (PIS), in which immune

Journal Pre-proof responses against antigens occur. Neoplasm can mediate autoimmunity by acting on both CIS and PIS. The thymus is a key immune organ in the CIS important to T cell development and differentiation. It is composed of a central medulla, a peripheral cortex and an outer capsule. During their development, T cells are first positively selected within the cortex and then further negatively selected within the medulla 91. Negative selection is an essential step that

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leads to the depletion of autoreactive T cells, a process key to central tolerance 91. Neoplasms

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can affect central tolerance by acting on thymic selection, leading to the generation of autoreactive T cells. One good example is a thymoma, which is composed of neoplastic

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thymic epithelial cells and non-neoplastic lymphocytes 92. The abnormal microenvironment of

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a thymoma, including its distorted architecture, low expression of MHC class II, and absence

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of expression of autoimmune regulator (AIRE) genes, leads to impaired positive and negative selection, resulting in the generation of autoreactive T cells 91;93.

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In addition, neoplasms can also affect the CIS by acting on the generation of regulatory T

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cells (Tregs). Tregs are essential players in the maintenance of immune tolerance to self-

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antigens and are comprised of two subgroups, naturally occurring Tregs, which are generated in the thymus, and induced Tregs, which are induced in the PIS

94;95

. Given that thymic

malignancies affect both the positive and the negative selection of T cells

91

, it is conceivable

that they could also affect the generation of naturally occurring Tregs. This notion is supported by the finding that the number of naturally occurring Tregs is considerably lower in MG-associated thymoma than in normal individuals 96. As a consequence, this lower number of naturally occurring Tregs could contribute to the autoimmunity observed in thymomaassociated autoimmune disorders. In addition to the CIS, the PIS can also be affected by neoplasms, resulting in autoimmunity and autoimmune disorders. Physiologically, peripheral immune tolerance to self-antigens is maintained via multiple strategies, including the activities of Tregs

97

and antigen-presenting

Journal Pre-proof cells (APCs) and anergy by autoreactive lymphocytes 98. In addition, neoplasms can decrease the Th17/Treg ratio, thereby leading to autoimmunity 99. Furthermore, neoplasms can trigger autoimmunity by acting on APCs. It has been shown that in both lymphoma and CLL, neoplastic cells express MHC and co-stimulatory molecules, making them immunogenic APCs and thereby leading to autoimmunity and autoimmune diseases 100-102. 3.1.2 Neoplasm-mediated dysregulated homeostasis in autoantigens

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In addition to acting on the immune system, neoplasms can also trigger autoimmunity by

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deregulating the homeostasis of autoantigens. First, genetic mutations in neoplastic cells

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could lead to the generation of neoantigens, which are able to trigger autoimmune responses. This notion is best exemplified in cancer-associated SSc with autoantibodies against RNAP 24.

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In 2014, Joseph and colleagues reported that patients with cancer-associated SSc carry non-

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synonymous genetic mutations in the RNAP gene. Interestingly, those mutations cause a change in the amino acid residues within T cell epitopes, leading to T cell immune responses

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against the mutant epitopes and autoantibodies against the whole RNAP antigen 24.

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Second, ectopic expression of proteins is another type of dysreguation of autoantigens that

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leads to autoimmunity. Under physiological conditions, some neuronal-specific antigens are only highly expressed in the CNS, which is an immune-privileged region103, and this leads to the escape of neuronal antigen-specific T cells from central tolerance

104

. Therefore, when

neuronal antigens are ectopically expressed at a high level within malignancies, e.g., NMDAR in teratoma

105

or Hu antigen

106

and neuronal presynaptic P/Q-VGCCs in SCLC

107

, this

ectopic expression could trigger autoimmune responses. Notably, although ectopic expression of neuronal antigens in malignancy is a common phenomenon, only a very small portion of patients with malignancies show autoimmunity and autoimmune diseases

106;107

, suggesting

that only ectopic expression of autoantigens might be insufficient to trigger autoimmunity.

Journal Pre-proof Finally, a malignant tumour microenvironment, such as tumour necrosis and inflammation, might lead to the abnormal release of autoantigens, which further triggers autoimmunity and the generation of a wide spectrum of autoantibodies, especially autoantibodies against intracellular autoantigens108-110. 3.1.3 Treatment-associated autoimmunity Apart from autoimmunity mediated by tumour itself, the association of paraneoplastic

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autoimmunity with cancer therapy needs to be taken into consideration. For example, it was

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reported that blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) with

patients with metastatic melanoma

111

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monoclonal antibody (MDX-010) induced autoimmune manifestations in more than 40% . Moreover, administration of blocking monoclonal

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antibodies against another co-inhibitory molecule, programmed death-1 (PD-1), could also 112;113

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lead to side-effects of autoimmune manifestations

. Therefore,

paraneoplastic

checkpoint inhibitors.

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autoimmunity can also be a consequence of cancer therapy, e.g. treatment with immune

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3.2 Pathogenesis of paraneoplastic autoimmune disorders

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Similar to many autoimmune disorders, the pathology of PAD can be mediated by autoantibodies and/or autoreactive T cells. In general, autoantibodies are able to mediate disease pathology via many mechanisms, including mimic receptor stimulation, the blocking of neural transmission, the induction of altered signalling, or by triggering uncontrolled microthrombosis, cell lysis, neutrophil activation, or the activation of the complement system and induction of inflammation 114. In T-cell-mediated disease pathologies, autoreactive T cells can exert their effects either by acting like a regulatory cell, e.g., helper T cells, which mediate inflammation, or by acting like an effector cell, e.g., cytotoxic T cells

115

.

The pathologies of most PAD with autoantibodies against extracellular antigens are mediated predominantly by autoantibodies, such as thymoma-associated MG, PAMS, paraneoplastic

Journal Pre-proof autoimmune cytopenias and various cancer-associated AEs. In some PADs, autoantibodies cause disease pathology via a single mechanism. For example, autoantibodies against NMDAR cause the dysfunction of the synaptic complex and subsequent disease symptoms by binding to a receptor to mediate receptor internalization

116

. Another example is

paraneoplastic PRCA, in which autoantibodies against erythropoietin prevent the binding of erythropoietin to its receptor and thus block the differentiation of erythroid progenitors

39

. In

some PADs, autoantibodies can mediate disease pathology via multiple mechanisms, and this

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f

process is well exemplified by thymoma-associated MG. In thymoma-associated MG, antiAChR antibodies are able to trigger three pathogenic mechanisms: 1) the activation of the

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complement system at the postsynaptic membrane, which leads to the formation of membrane

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attack complexes; 2) by binding and crosslinking postsynaptic AChRs, which results in

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increased endocytosis and degradation; and 3) by preventing the binding of ACh to the AchR 117

.

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Apart from extracellular antigens, a small portion of intracellular autoantigens could also be

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the targets of autoantibodies that mediate the disease pathology of PAD. One good example is

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anti-amphiphysin in paraneoplastic SPS. Amphiphysin, a protein in the BAR superfamily, plays a crucial role in clathrin-mediated endocytosis, which is required for the recycling of synaptic vesicles

118

. During synaptic vesicle fusion and reuptake, intracellular amphiphysin

can be exposed to and bound by autoantibodies, and this binding leads to the dysfunction of synaptic complexes and disease symptoms 119. In most PAD with autoantibodies against intracellular molecules, due to a lack of access to antigens, the autoantibodies are not able to mediate disease pathology. Therefore, it is conceivable that the disease pathology of those PAD are mainly mediated by T cells. This hypothesis is supported by evidence obtained in PCD and PEM, which are characterized by autoantibodies against intracellular antigens. For example, in patients with PEM featuring anti-Hu antibodies, T-cell responses to Hu antigen have been demonstrated

120

. Furthermore,

Journal Pre-proof Bernal et al. demonstrated that in affected patients, a large number of cytotoxic T cells are irregularly distributed in the brain parenchyma, usually in clusters and often around neurons expressing MHC I molecules

121

, suggesting a role for cytotoxic T cells in the disease

pathogenesis. In addition, T-cell receptor analysis also supports a role for antigen-driven oligoclonal cytotoxic T-cell responses in the pathogenesis of anti-Hu-associated PEM

79

.

Apart from cytotoxic T cells, autoreactive CD4+ T cells against the Hu antigen have also been

f

observed in patients with PEM, but their role in this disease pathogenesis remains unclear122.

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Notably, the disease pathology of some PAD involves contributions from both arms of

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autoimmune responses, as exemplified by paraneoplastic AITP, an autoimmune disease caused by abnormal autoimmune responses against platelets. Autoantibodies against platelets

e-

facilitate platelet phagocytosis by macrophages, and autoreactive CD8+ T cells can also

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mediate platelet apoptosis 42. 4 Conclusion and perspectives

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PAD represents a rapidly evolving field of autoimmune disorders. Due to neoplasm-triggered

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autoimmunity, PAD differ from non-neoplastic autoimmune diseases in many ways, such as 14;19

. Therefore, it is

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their aetiology, pathology, disease symptoms and treatment responses

important that PAD are properly diagnosed, recognized and investigated. In the past decade, considerable progress has been achieved in increasing our understanding of the aetiology and pathology of PAD, particularly for those predominantly mediated by autoantibodies 70;117. Further deciphering the aetiology and pathogenesis of PAD will lead to better treatments of those disorders. Take-home message PAD are a group of disorders mediated by neoplasm-associated autoimmunity. Neoplasm might trigger autoimmunity by disturbing the homeostasis of the immune system and/or autoantigens.

Journal Pre-proof According to their pathomechanism, PAD can be categorized into two major groups:

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autoantibody-mediated and autoreactive T-cell-mediated diseases.

Journal Pre-proof Acknowledgements This work was supported by Department of Science and technology of Xiamen City，China (No. 3502z20189007) and by the Deutsche Forschungsgemeinschaft: Research Training Group “Modulation of Autoimmunity” (GRK1727) and the German Center for Lung

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Research (DZL).

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Author contributions

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All authors wrote the manuscript.

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The authors declare no conflict of interest.

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.Competing financial interests

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Reference

1. Dahan S, Segal Y, Watad A et al. Novelties in the field of autoimmunity - 1st Saint Petersburg congress of autoimmunity, the bridge between east and west. Autoimmun.Rev.

f

2017;16:1175-1184.

oo

2. Cheng M, Anderson MS. Thymic tolerance as a key brake on autoimmunity. Nat.Immunol.

pr

2018;19:659-664.

e-

3. Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery.

Pr

Nat.Rev.Immunol. 2002;2:11-19.

4. Theofilopoulos AN, Kono DH, Baccala R. The multiple pathways to autoimmunity.

al

Nat.Immunol. 2017;18:716-724.

rn

5. Maley CC, Aktipis A, Graham TA et al. Classifying the evolutionary and ecological features of

Jo u

neoplasms. Nat.Rev.Cancer 2017;17:605-619.

6. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat.Rev.Cancer 2006;6:24-37.

7. Wang X, Yu J, Sreekumar A et al. Autoantibody signatures in prostate cancer. N.Engl.J.Med. 2005;353:1224-1235.

8. Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res. 2012;32:1119-1136.

9. Turesson C, Matteson EL. Malignancy as a comorbidity in rheumatic diseases. Rheumatology.(Oxford) 2013;52:5-14.

Journal Pre-proof 10. Yu KH, Kuo CF, Huang LH, Huang WK, See LC. Cancer Risk in Patients With Inflammatory Systemic Autoimmune Rheumatic Diseases: A Nationwide Population-Based Dynamic Cohort Study in Taiwan. Medicine (Baltimore) 2016;95:e3540.

11. Giat E, Ehrenfeld M, Shoenfeld Y. Cancer and autoimmune diseases. Autoimmun.Rev. 2017;16:1049-1057.

12. Narvaez J, Juarez-Lopez P, LLuch J et al. Rheumatic immune-related adverse events in

oo

f

patients on anti-PD-1 inhibitors: Fasciitis with myositis syndrome as a new complication of immunotherapy. Autoimmun.Rev. 2018;17:1040-1045.

pr

13. Amber KT, Valdebran M, Grando SA. Paraneoplastic autoimmune multiorgan syndrome

e-

(PAMS): Beyond the single phenotype of paraneoplastic pemphigus. Autoimmun.Rev.

Pr

2018;17:1002-1010.

14. Rosenfeld MR, Dalmau J. Paraneoplastic Neurologic Syndromes. Neurol.Clin. 2018;36:675-

rn

al

685.

15. Amber KT, Valdebran M, Grando SA. Paraneoplastic autoimmune multiorgan syndrome

Jo u

(PAMS): Beyond the single phenotype of paraneoplastic pemphigus. Autoimmun.Rev. 2018;17:1002-1010.

16. Benvenuto M, Mattera R, Masuelli L et al. The crossroads between cancer immunity and autoimmunity: antibodies to self antigens. Front Biosci.(Landmark.Ed) 2017;22:1289-1329.

17. Anhalt GJ, Kim SC, Stanley JR et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N.Engl.J.Med. 1990;323:1729-1735.

18. Mimouni D, Anhalt GJ, Lazarova Z et al. Paraneoplastic pemphigus in children and adolescents. Br.J.Dermatol. 2002;147:725-732.

Journal Pre-proof 19. Amber KT, Valdebran M, Grando SA. Paraneoplastic autoimmune multiorgan syndrome (PAMS): Beyond the single phenotype of paraneoplastic pemphigus. Autoimmun.Rev. 2018;17:1002-1010.

20. Joly P, Richard C, Gilbert D et al. Sensitivity and specificity of clinical, histologic, and immunologic features in the diagnosis of paraneoplastic pemphigus. J.Am.Acad.Dermatol. 2000;43:619-626.

oo

f

21. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N.Engl.J.Med. 2009;360:1989-2003.

22. Moinzadeh P, Fonseca C, Hellmich M et al. Association of anti-RNA polymerase III

e-

pr

autoantibodies and cancer in scleroderma. Arthritis Res.Ther. 2014;16:R53.

23. Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L. Close temporal relationship

Pr

between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies.

al

Arthritis Rheum. 2010;62:2787-2795.

rn

24. Joseph CG, Darrah E, Shah AA et al. Association of the autoimmune disease scleroderma with

Jo u

an immunologic response to cancer. Science 2014;343:152-157.

25. Wadhera A, Maverakis E, Mitsiades N et al. Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease. J.Am.Acad.Dermatol. 2007;57:683-689.

26. Holder J, North J, Bourke J et al. Thymoma-associated cutaneous graft-versus-host-like reaction. Clin.Exp.Dermatol. 1997;22:287-290.

27. Kornacki S, Hansen FC, III, Lazenby A. Graft-versus-host-like colitis associated with malignant thymoma. Am.J.Surg.Pathol. 1995;19:224-228.

28. Warren S, Nehal K, Querfeld C et al. Graft-versus-host disease-like erythroderma: a manifestation of thymoma-associated multiorgan autoimmunity. J.Cutan.Pathol. 2015;42:663-668.

Journal Pre-proof 29. Ichiki Y, Bowlus CL, Shimoda S et al. T cell immunity and graft-versus-host disease (GVHD). Autoimmun.Rev. 2006;5:1-9.

30. Gunawardena DA, Gunawardena KA, Ratnayaka RM, Vasanthanathan NS. The clinical spectrum of Sweet's syndrome (acute febrile neutrophilic dermatosis)-a report of eighteen cases. Br.J.Dermatol. 1975;92:363-373.

31. Maverakis E, Le ST, Callen J et al. New validated diagnostic criteria for pyoderma

oo

f

gangrenosum. J.Am.Acad.Dermatol. 2018

32. Marzano AV, Fanoni D, Antiga E et al. Expression of cytokines, chemokines and other effector

pr

molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and

e-

Sweet's syndrome. Clin.Exp.Immunol. 2014;178:48-56.

Pr

33. Marzano AV, Borghi A, Meroni PL, Cugno M. Pyoderma gangrenosum and its syndromic

al

forms: evidence for a link with autoinflammation. Br.J.Dermatol. 2016;175:882-891.

rn

34. Win N, Tiwari D, Keevil VL, Needs M, Lakhani A. Mixed-type autoimmune haemolytic anaemia: unusual cases and a case associated with splenic T-cell angioimmunoblastic non-

Jo u

Hodgkin's lymphoma. Hematology. 2007;12:159-162.

35. Hauswirth AW, Skrabs C, Schutzinger C et al. Autoimmune hemolytic anemias, Evans' syndromes, and pure red cell aplasia in non-Hodgkin lymphomas. Leuk.Lymphoma 2007;48:1139-1149.

36. Visco C, Barcellini W, Maura F et al. Autoimmune cytopenias in chronic lymphocytic leukemia. Am.J.Hematol. 2014;89:1055-1062.

37. Puthenparambil J, Lechner K, Kornek G. Autoimmune hemolytic anemia as a paraneoplastic phenomenon in solid tumors: A critical analysis of 52 cases reported in the literature. Wien.Klin.Wochenschr. 2010;122:229-236.

Journal Pre-proof 38. Means RT, Jr. Pure red cell aplasia. Blood 2016;128:2504-2509.

39. Casadevall N, Dupuy E, Molho-Sabatier P et al. Autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N.Engl.J.Med. 1996;334:630-633.

40. George JN. Definition, diagnosis and treatment of immune thrombocytopenic purpura. Haematologica 2009;94:759-762.

f

41. Rodeghiero F, Stasi R, Gernsheimer T et al. Standardization of terminology, definitions and

oo

outcome criteria in immune thrombocytopenic purpura of adults and children: report from

pr

an international working group. Blood 2009;113:2386-2393.

e-

42. Audia S, Mahevas M, Samson M, Godeau B, Bonnotte B. Pathogenesis of immune

Pr

thrombocytopenia. Autoimmun.Rev. 2017;16:620-632.

43. Krauth MT, Puthenparambil J, Lechner K. Paraneoplastic autoimmune thrombocytopenia in

al

solid tumors. Crit Rev.Oncol.Hematol. 2012;81:75-81.

rn

44. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic

Jo u

strategies. Lancet Neurol. 2015;14:1023-1036.

45. Marx A, Pfister F, Schalke B et al. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun.Rev. 2013;12:875-884.

46. Fukuhara M, Higuchi M, Owada Y et al. Clinical and pathological aspects of microscopic thymoma with myasthenia gravis and review of published reports. J.Thorac.Dis. 2017;9:15921597.

47. Schoser B, Eymard B, Datt J, Mantegazza R. Lambert-Eaton myasthenic syndrome (LEMS): a rare autoimmune presynaptic disorder often associated with cancer. J.Neurol. 2017;264:1854-1863.

Journal Pre-proof 48. Katz E, Ferro PA, Weisz G, Uchitel OD. Calcium channels involved in synaptic transmission at the mature and regenerating mouse neuromuscular junction. J.Physiol 1996;497 ( Pt 3):687697.

49. Hajela RK, Huntoon KM, Atchison WD. Lambert-Eaton syndrome antibodies target multiple subunits of voltage-gated Ca2+ channels. Muscle Nerve 2015;51:176-184.

50. Abenroth DC, Smith AG, Greenlee JE, Austin SD, Clardy SL. Lambert-Eaton myasthenic

oo

f

syndrome: Epidemiology and therapeutic response in the national veterans affairs population. Muscle Nerve 2017;56:421-426.

pr

51. Wirtz PW, Smallegange TM, Wintzen AR, Verschuuren JJ. Differences in clinical features

e-

between the Lambert-Eaton myasthenic syndrome with and without cancer: an analysis of

Pr

227 published cases. Clin.Neurol.Neurosurg. 2002;104:359-363.

52. Payne M, Bradbury P, Lang B et al. Prospective study into the incidence of Lambert Eaton

rn

al

myasthenic syndrome in small cell lung cancer. J.Thorac.Oncol. 2010;5:34-38.

53. Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. Phenotypic variants of

Jo u

autoimmune peripheral nerve hyperexcitability. Brain 2002;125:1887-1895.

54. Vernino S, Lennon VA. Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability. Muscle Nerve 2002;26:702-707.

55. Liebenthal JA, Rezania K, Nicholas MK, Lukas RV. Paraneoplastic nerve hyperexcitability. Neurol.Res. 2015;37:553-559.

56. Grange L, Dalal M, Nussenblatt RB, Sen HN. Autoimmune retinopathy. Am.J.Ophthalmol. 2014;157:266-272.

57. Forooghian F, Macdonald IM, Heckenlively JR et al. The need for standardization of antiretinal antibody detection and measurement. Am.J.Ophthalmol. 2008;146:489-495.

Journal Pre-proof 58. Weleber RG, Watzke RC, Shults WT et al. Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies. Am.J.Ophthalmol. 2005;139:780-794.

59. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC.Ophthalmol. 2004;4:5.

60. Adamus G, Machnicki M, Elerding H et al. Antibodies to recoverin induce apoptosis of

oo

f

photoreceptor and bipolar cells in vivo. J.Autoimmun. 1998;11:523-533.

61. Ren G, Adamus G. Cellular targets of anti-alpha-enolase autoantibodies of patients with

e-

pr

autoimmune retinopathy. J.Autoimmun. 2004;23:161-167.

62. Shams'ili S, Grefkens J, de LB et al. Paraneoplastic cerebellar degeneration associated with

Pr

antineuronal antibodies: analysis of 50 patients. Brain 2003;126:1409-1418.

al

63. Schwenkenbecher P, Chacko L, Pul R et al. Paraneoplastic cerebellar syndromes associated

rn

with antibodies against Purkinje cells. Int.J.Neurosci. 2018;128:721-728.

Jo u

64. Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 1992;42:1931-1937.

65. Tanaka M, Tanaka K, Shinozawa K, Idezuka J, Tsuji S. Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. J.Neurol.Sci. 1998;161:88-90.

66. Bernal F, Shams'ili S, Rojas I et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology 2003;60:230-234.

67. de GE, Maat P, Hulsenboom E et al. Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. Ann.Neurol. 2012;71:815-824.

Journal Pre-proof 68. Dalmau J, Rosenfeld MR. Autoimmune encephalitis update. Neuro.Oncol. 2014;16:771-778.

69. Oldham M. Autoimmune Encephalopathy for Psychiatrists: When to Suspect Autoimmunity and What to Do Next. Psychosomatics 2017;58:228-244.

70. Dalmau J, Graus F. Antibody-Mediated Encephalitis. N.Engl.J.Med. 2018;378:840-851.

71. Dalmau J, Tuzun E, Wu HY et al. Paraneoplastic anti-N-methyl-D-aspartate receptor

oo

f

encephalitis associated with ovarian teratoma. Ann.Neurol. 2007;61:25-36.

72. Florance NR, Davis RL, Lam C et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis

pr

in children and adolescents. Ann.Neurol. 2009;66:11-18.

e-

73. van SA, Thijs RD, Coenders EC et al. Anti-LGI1 encephalitis: Clinical syndrome and long-term

Pr

follow-up. Neurology 2016;87:1449-1456.

74. Shu Y, Qiu W, Zheng J et al. HLA class II allele DRB1*16:02 is associated with anti-NMDAR

rn

al

encephalitis. J.Neurol.Neurosurg.Psychiatry 2019

75. Kim TJ, Lee ST, Moon J et al. Anti-LGI1 encephalitis is associated with unique HLA subtypes.

Jo u

Ann.Neurol. 2017;81:183-192.

76. Grativvol RS, Cavalcante WCP, Castro LHM, Nitrini R, Simabukuro MM. Updates in the Diagnosis and Treatment of Paraneoplastic Neurologic Syndromes. Curr.Oncol.Rep. 2018;20:92.

77. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu--associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 1992;71:59-72.

78. Graus F, Keime-Guibert F, Rene R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148.

Journal Pre-proof 79. Voltz R, Dalmau J, Posner JB, Rosenfeld MR. T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 1998;51:1146-1150.

80. Honnorat J, Cartalat-Carel S, Ricard D et al. Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J.Neurol.Neurosurg.Psychiatry 2009;80:412-416.

81. Vogrig A, Joubert B, Maureille A et al. Motor neuron involvement in anti-Ma2-associated

oo

f

paraneoplastic neurological syndrome. J.Neurol. 2018

82. Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia

e-

pr

syndrome. Curr.Opin.Pediatr. 2010;22:745-750.

83. Blaes F, Dharmalingam B. Childhood opsoclonus-myoclonus syndrome: diagnosis and

Pr

treatment. Expert.Rev.Neurother. 2016;16:641-648.

al

84. Buckanovich RJ, Yang YY, Darnell RB. The onconeural antigen Nova-1 is a neuron-specific

rn

RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies.

Jo u

J.Neurosci. 1996;16:1114-1122.

85. Xin Y, Li Z, Zheng H et al. Neuro-oncological ventral antigen 1 (NOVA1): Implications in neurological diseases and cancers. Cell Prolif. 2017;50:

86. Baizabal-Carvallo JF, Jankovic J. Stiff-person syndrome: insights into a complex autoimmune disorder. J.Neurol.Neurosurg.Psychiatry 2015;86:840-848.

87. Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008;71:1955-1958.

88. De CP, Thomas A, Cofiell R et al. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer. J.Exp.Med. 1993;178:22192223.

Journal Pre-proof 89. Lichte B, Veh RW, Meyer HE, Kilimann MW. Amphiphysin, a novel protein associated with synaptic vesicles. EMBO J. 1992;11:2521-2530.

90. Petersen F, Yue X, Riemekasten G, Yu X. Dysregulated homeostasis of target tissues or autoantigens - A novel principle in autoimmunity. Autoimmun.Rev. 2017;16:602-611.

91. Weksler B, Lu B. Alterations of the immune system in thymic malignancies. J.Thorac.Oncol.

f

2014;9:S137-S142.

oo

92. den Bakker MA, Roden AC, Marx A, Marino M. Histologic classification of thymoma: a

pr

practical guide for routine cases. J.Thorac.Oncol. 2014;9:S125-S130.

e-

93. Nenninger R, Schultz A, Hoffacker V et al. Abnormal thymocyte development and generation

Pr

of autoreactive T cells in mixed and cortical thymomas. Lab Invest 1998;78:743-753.

94. Hsieh CS, Lee HM, Lio CW. Selection of regulatory T cells in the thymus. Nat.Rev.Immunol.

al

2012;12:157-167.

rn

95. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human

Jo u

immune system. Nat.Rev.Immunol. 2010;10:490-500.

96. Luther C, Poeschel S, Varga M, Melms A, Tolosa E. Decreased frequency of intrathymic regulatory T cells in patients with myasthenia-associated thymoma. J.Neuroimmunol. 2005;164:124-128.

97. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775-787.

98. Mueller DL. Mechanisms maintaining peripheral tolerance. Nat.Immunol. 2010;11:21-27.

Journal Pre-proof 99. Lad DP, Varma S, Varma N et al. Regulatory T-cell and T-helper 17 balance in chronic lymphocytic leukemia progression and autoimmune cytopenias. Leuk.Lymphoma 2015;56:2424-2428.

100. Cycon KA, Clements JL, Holtz R, Fuji H, Murphy SP. The immunogenicity of L1210 lymphoma clones correlates with their ability to function as antigen-presenting cells. Immunology 2009;128:e641-e651.

oo

f

101. Thompson ED, Enriquez HL, Fu YX, Engelhard VH. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J.Exp.Med. 2010;207:1791-1804.

pr

102. Tomic J, White D, Shi Y et al. Sensitization of IL-2 signaling through TLR-7 enhances B

e-

lymphoma cell immunogenicity. J.Immunol. 2006;176:3830-3839.

al

Immunol. 2015;36:569-577.

Pr

103. Louveau A, Harris TH, Kipnis J. Revisiting the Mechanisms of CNS Immune Privilege. Trends

Jo u

2009;9:393-407.

rn

104. Goverman J. Autoimmune T cell responses in the central nervous system. Nat.Rev.Immunol.

105. Tachibana N, Shirakawa T, Ishii K et al. Expression of various glutamate receptors including Nmethyl-D-aspartate receptor (NMDAR) in an ovarian teratoma removed from a young woman with anti-NMDAR encephalitis. Intern.Med. 2010;49:2167-2173.

106. Dalmau J, Graus F, Cheung NK et al. Major histocompatibility proteins, anti-Hu antibodies, and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 1995;75:99-109.

107. McCann FV, Pettengill OS, Cole JJ, Russell JA, Sorenson GD. Calcium spike electrogenesis and other electrical activity in continuously cultured small cell carcinoma of the lung. Science 1981;212:1155-1157.

Journal Pre-proof 108. bu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y. Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann.Rheum.Dis. 2001;60:433-441.

109. Gogas H, Ioannovich J, Dafni U et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N.Engl.J.Med. 2006;354:709-718.

f

110. Nanda NK, Sercarz EE. Induction of anti-self-immunity to cure cancer. Cell 1995;82:13-17.

oo

111. Phan GQ, Yang JC, Sherry RM et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.

e-

pr

Proc.Natl.Acad.Sci.U.S.A 2003;100:8372-8377.

112. Hofmann L, Forschner A, Loquai C et al. Cutaneous, gastrointestinal, hepatic, endocrine, and

Pr

renal side-effects of anti-PD-1 therapy. Eur.J.Cancer 2016;60:190-209.

al

113. Zimmer L, Goldinger SM, Hofmann L et al. Neurological, respiratory, musculoskeletal, cardiac

rn

and ocular side-effects of anti-PD-1 therapy. Eur.J.Cancer 2016;60:210-225.

Jo u

114. Ludwig RJ, Vanhoorelbeke K, Leypoldt F et al. Mechanisms of Autoantibody-Induced Pathology. Front Immunol. 2017;8:603.

115. Pilli D, Zou A, Tea F, Dale RC, Brilot F. Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System. Front Immunol. 2017;8:652.

116. Moscato EH, Peng X, Jain A et al. Acute mechanisms underlying antibody effects in anti-Nmethyl-D-aspartate receptor encephalitis. Ann.Neurol. 2014;76:108-119.

117. Verschuuren JJ, Huijbers MG, Plomp JJ et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun.Rev. 2013;12:918-923.

Journal Pre-proof 118. Wu Y, Matsui H, Tomizawa K. Amphiphysin I and regulation of synaptic vesicle endocytosis. Acta Med.Okayama 2009;63:305-323.

119. Pittock SJ, Lucchinetti CF, Parisi JE et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann.Neurol. 2005;58:96-107.

120. Rousseau A, Benyahia B, Dalmau J et al. T cell response to Hu-D peptides in patients with

f

anti-Hu syndrome. J.Neurooncol. 2005;71:231-236.

oo

121. Bernal F, Graus F, Pifarre A et al. Immunohistochemical analysis of anti-Hu-associated

pr

paraneoplastic encephalomyelitis. Acta Neuropathol. 2002;103:509-515.

e-

122. Benyahia B, Liblau R, Merle-Beral H et al. Cell-mediated autoimmunity in paraneoplastic

Jo u

rn

al

Pr

neurological syndromes with anti-Hu antibodies. Ann.Neurol. 1999;45:162-167.

Journal Pre-proof Table 1: Autoimmune disorders associated with tumours that affect the immune system. Targeted autoantigens

Mainly associated cancer

Reference

Paraneoplastic autoimmune multiorgan syndrome (PAMS)

Suprabasal acantholysis， subepdermal blistering, keratinocytes necrosis, ocular complications, muscle weakness, complications in the respiratory system and the gastrointestinal tract Fibrosis, vasculopathy

Plakins, desmoglein 1, desmoglein 3,BP antigen (230 kDa), BP antigen (180 kDa), cadherins, A2 ML1, plakophilin-3

Thymoma, lymphoma, CLL

17;19

RNA polymerase III

22-24

GVHD-like symptoms in the skin, liver and intestine.

Unknown

Breast, haematological, gastrointestinal and gynaecological cancer Thymoma

Anaemia

Red blood cell membrane antigens

CLL, lymphoma

34-37

Erythroprotein

CLL, thymoma

36;38;39

CLL, lymphoma, breast cancer, renal cell cancer, ovarian cancer

36;42;43

Thymoma

44-46

SCLC

47-52

SCLC, thymoma

53-55

Cancer-associated systemic sclerosis

Paraneoplastic autoimmune haematologic manifestations

Thymoma-associated multiorgan autoimmunity diseas e Paraneoplastic autoimmune haemolytic anaemia Paraneoplastic pure red cell aplasia

Anaemia Thrombocytopenia

Platelet autoantigens

Cancer associated Lambert-Eaton myasthenic syndrome Paraneoplastic peripheral nerve hyperexcitability syndromes

Fatigable muscle weakness

P/Q type VGCCs

Neuromuscular hyperexcitability

VGKC

Vision loss

Recoverin, alpha-enolase

Melanoma, breast cancer, SCLC

56-61

Yo (CDR 2)

Breast and gynaecological cancer

63-65

Tr (DNER)

Lymphoma

66;67

Memory loss, seizures, and psychiatric symptoms, abnormal movements, hypoventilation

NMDAR

Teratoma

71;72

LGI1

Thymoma

68;73

Limb encephalitis, PCD, rhomboencephalitis, sensory neuronopathy, myelitis and sympathetic and parasympathetic ganglia and nerves

ANNA1

SCLC

77;78

Ma2

Testicular germ cell tumours

81

CRMP5

SCLC

80

Paraneoplastic opsoclonus myoclonus syndrome

opsoclonus, myoclonus, and ataxia

NOVA1

Neuroblastoma, breast cancer, SCLC

82-84

Paraneoplastic Stiff-person syndrome

Stiffness in axial and limb muscles

Amphiphysin

Breast cancer

87;88

rn

al

Pr

Muscle weakness, muscle fatigue

Paraneoplastic autoimmune retinopathy Paraneoplastic cerebellar degeneration

Paraneoplastic autoimmune encephalitis

Paraneoplastic encephalomyelitis

Ataxia, dysarthria and intention tremor.

AChR

27-29

Thymoma-associated myasthenia gravis

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Paraneoplastic autoimmune manifestations in the central nervous system

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Paraneoplastic autoimmun e thrombocytopenia Paraneoplastic autoimmune manifestations in the peripheral nervous system

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Clinical manifestations

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Paraneoplastic autoimmune cutaneous manifestations

Paraneoplastic autoimmune disorders

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Paraneoplastic autoimmune disorders

A2ML1, alpha-2-macroglobulin like 1; AChR, acetylcholine receptor; ANNA1, type 1 antineuronal nuclear antibody; BP, bollous pemphigoid; CLL, Chronic lymphocytic leukaemia; SCLC, small cell lung cancer; CDR2, Cerebellar degeneration-related protein 2; CRMP5，anti-collapsin response mediator protein 5; DNER, delta/notch-like epidermal growth factor-related receptor; GVHD, graft-versushost disease; LGI1, leucine-rich-glioma-inactivated protein 1; NMDAR, N-methyl-D-aspartate receptor; NOVA1, neuro-oncological ventral antigen 1; PCD, paraneoplastic cerebellar degeneration; SCLC, small cell lung cancer; VGCCs, voltage-gated calcium channels; VGKC, voltage-gated potassium channel.