An autoimmune perspective on neuromuscular diseases

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1 An autoimmune perspective on neuromuscular diseases Colin Chalk MD,CM FRCPC Montreal General Hospital McGill University

2 Schlomchik 2001

3 The proportion of neuromuscular patients who have an autoimmune cause varies according to the site of the problem:

4

5 But polyneuropathy is much more common than disorders of muscle or neuro muscular junction. Hence, the number of autoimmune patients in the clinic is more like this:

6

7 Schlomchik 2001

8 The complete picture of an autoimmune disorder d should include: Trigger or precipitant of the autoimmune process Target of the autoimmune attack Mechanism of the autoimmune attack Natural history of the process Specific treatment based on the above

9

10 How completely do we understand myasthenia gravis? Trigger or precipitant: Unknown for most; 20% associated with thymoma Target: acetylcholine receptor Mechanism: Autoantibodies which reduce the number of AChR

11 NORMAL MYASTHENIA GRAVIS Copyright Wolters Kluwer (2008)

12 How completely do we understand myasthenia gravis? Trigger or precipitant: Unknown for most; 20% associated with thymoma Target: acetylcholine receptor Mechanism: Autoantibodies which reduce the number of AChR Natural history: Variable and unpredictable Specific treatments: NO

13 How completely do we understand Guillain Barré syndrome? Trigger or precipitant: Preceding infection in most patients (Campylobacter, etc) Target: Myelin (gangliosides) or internodal membrane components (many suspects) Mechanism: Probably bl multiple, li l with ihsome evidence for molecular mimicry

14 Differences in immunopathogenesis of axonal and demyelinating GBS (Kuwabara 2013)

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16 How completely do we understand Guillain Barré syndrome? Trigger or precipitant: Preceding infection in most patients (Campylobacter, etc) Target: Myelin or internodal membrane components (many suspects) Mechanism: Probably bl multiple, li l with ihsome evidence for molecular mimicry Natural history: Monophasic and self limited Specific treatments: NO

17 How completely do we understand dermatomyositis? Trigger or precipitant: Unknown in most; cancer (lung, ovary) in some. Target:?muscle microvasculature Mechanism:? ( myositis specific antibodies in some, role controversial) il)

18 Except for amyopathic cases, muscle biopsy is critical for the diagnosis of DM. The earliest detectable histologic abnormality on light microscopy in DM is deposition of the C5b-9 or MAC of complement around small blood vessels.69,70 This humorally mediated microangiopathy leads to decreased capillary density, especially at the periphery of the fascicle. It is fairly characteristic of DM, and may explain the occasional infarction of muscle fibers in JDM. MAC deposition is highly sensitive and specific in differentiating DM from other IIM. Capillary damage and myofiber atrophy are concentrated in regions distant from the affected intermediate-sized perimysial vessels, leading to the suggestion that watershed ischemia is the cause of myofiber atrophy and capillary damage in regions of muscle near the avascular perimysium.71 The interferon (IFN)-a/b inducible protein, myxovirus resistance (MxA), was recently found to be expressed in 90% of capillaries.72,73 Nearly half of muscle biopsies demonstrate perifascicular atrophy (Fig. 2), often without an inflammatory infiltrate. When present, the inflammatory infiltrate consists of predominantly perimysial and perivascular macrophages and B cells presenting a putative antigen to naı ve CD41 cells, some of which are T lymphocytes but most of which are plasmacytoid dendritic cells (pdc) (see Fig. 2). Invasion of nonnecrotic fibers is not common. The incidence of rare infiltrative lesions in those with malignant tumors (45%) was significantly higher than in those without such tumors (14%). The end result of this humoral microangiopathy is myofibril necrosis in groups, and regeneration. The presentation is HLA class II restricted, and leads to the maturation of CD41 T cells and pdc, depending on the cytokine environment, into T-helper type 1 (Th1), Th2, Th17, or regulatory T cells (Treg). Th1 and Th17 activation produce proinflammatory cytokines present in myositis tissues, and are associated with the migration, differentiation, and maturation of inflammatory cells, including dendritic cells (DC). Natural Tregs are CD41CD251 FoxP31, whereas adaptive Tregs are induced in the peripheral immune system after encountering foreign antigens and have 2 distinct cytokine profiles. Type 1 Tregs secrete high levels of IL-10, whereas Th3 cells secrete high levels of the profibrotic agent transforming growth factor (TGF)-b.74 Antiga and colleagues75 found that the number of Treg cells in the peripheral blood of patients with DM was significantly reduced when compared with healthy controls, with a reduction in TGF-b and IL-10 serum levels suggesting that Treg depletion may be an important factor in the pathogenesis of the disease. FOXP31 Tregs are found in close proximity to effector cells, and serve to counterbalance muscle destruction by cytotoxic T cells in myositis.76 Fascin-positive DC predominance in inflammatory infiltrates in both PM and DM muscles confirms the prevalence of mature forms and indicates that there is stimulation of DC maturation.77 On EM, the earliest recognized changes are tubuloreticular inclusions in the intramuscular arterioles and capillaries.78 MxA colocalizes to the small intramuscular blood vessel inclusions, and is thought to form tubuloreticular inclusions around RNA Recent evidence from DM muscle derived microarray studies has uncovered an increase in MHC-1 and immunoglobulin gene transcripts79 and a robust increase in the expression of IFN1-inducible genes up to 570-fold, in addition to an abundant immunoglobulin gene transcript.72 The expression of MxA is localized to 50% perifascicular muscle fibers in addition to diffuse perifascicular MHC-1 positivity. MxA, as the name indicates, is inducible by IFN1s. IFN1s are known to upregulate MHC expression, activate natural killer cell cytotoxicity, promote activated T-cell survival, and support DC maturation. Analysis of peripheral blood mononuclear cells demonstrates a high IFN-a/b signature, which parallels disease activity in DM.80 IL-6, a proinflammatory cytokine, plays central roles in the regulation of both innate and adaptive inflammatory and immune responses, in addition to both humoral and cell-mediated autoimmune

19 How completely do we understand dermatomyositis? Trigger or precipitant: Unknown in most; cancer (lung, ovary) in some. Target:?muscle microvasculature Mechanism:? ( myositis specific antibodies in some, role controversial) il) Natural history: Chronic, progressive Specific treatments: NO

20

21 Treatments for autoimmune neuromuscular diseases Theideal: therapy targeting disease specific specific immune mechanism(s). Still elusive In MG, use of pyridostigmine (Mestinon) is based on disease pathophysiology, although not its immune mechanism. The reality: non specific immunotherapies Corticosteroids Immunosuppressants Biologicals IVIg, plasma exchange

22 Asking Could this be autoimmune? in the neuromuscular clinic has potentially important consequences. Patient s disease may prove to be treatable BUT, once therapy is started, it is often very difficult to stop. At leasti m Im not getting worse! Placebo effect: especially an issue with IVIg and plasma exchange. Distinguishing gbetween improved neuromuscular function and I just feel better takes time, and can even become a source of conflict between patients and physicians.

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