Autoimmune Diseases Flashcards

Question

Give examples of indirect evidence of autoimmunity

Answer 1

Thyroiditis and multiple sclerosis can be reproduced by immunizing the animal with an antigen analogous to the putative autoantigen of the human disease

Answer 2

Myasthenia gravis is an autoimmune condition that affects the nerves and muscles, and causes certain muscles to become weak (mainly voluntarily controlled muscles)

Answer 3

Progressive weakness and fatigability of striated muscles Proximal muscles are most often affected and weakness in ocular muscles results in ptosis and diplopia. Associated symptoms include depressed or absent reflexes and decreasing amplitude of responses on repetitive nerve stimulation.

Answer 4

MG can occur at any age, but is most commonly seen in women during the third and fourth decades and in middle-aged men.

Answer 5

Injection of edrophonium causes a transient resolution of symptoms.

Answer 6

It is associated with other autoimmune disorders and hyperthyroidism.

Answer 7

Lambert-Eaton myasthenic syndrome (LEMS)

Answer 8

An autoimmune, often paraneoplastic condition in which antibodies are produced against presynaptic calcium channels, preventing the release of acetylcholine (ACh).

Answer 9

Blocking ACh receptors | Degrading ACh receptors

Answer 10

Short acting acetylcholinesterase inhibitor

Answer 11

There is a reduction in the number of AChRs available at the muscle endplate and flattening of the postsynaptic folds. Consequently, even if a normal amount of ACh is released, fewer endplate potentials will be produced, and they may fall below the threshold value for generation of an action potential. The end result of this process is inefficient neuromuscular transmission.

Answer 12

Inefficient neuromuscular transmission together with the normally present presynaptic rundown phenomenon results in a progressive decrease in the amount of nerve fibers being activated by successive nerve fiber impulses. This explains the fatigability seen in MG patients.

Answer 13

Cross-linking 2 adjacent AChRs with anti-AChR antibody, thus accelerating internalization and degradation of AChR molecules Causing complement-mediated destruction of junctional folds of the postsynaptic membrane Blocking the binding of ACh to AChR Decreasing the number of AChRs at the NMJ by damaging the junctional folds on the postsynaptic membrane, thereby reducing the surface area available for insertion of newly synthesized AChRs

Answer 14

Patients without anti-AChR antibodies are recognized as having seronegative MG (SNMG).

Answer 15

Many patients with SNMG have antibodies against muscle-specific kinase (MuSK). MuSK plays a critical role in postsynaptic differentiation and clustering of AChRs. Patients with anti-MuSK antibodies are predominantly female, and respiratory and bulbar muscles are frequently involved. Another group has reported patients who exhibit prominent neck, shoulder, and respiratory weakness

Answer 16

The role of the thymus in the pathogenesis of MG is not entirely clear, but histopathologic studies have shown prominent germinal centers. Epithelial myoid cells normally present in the thymus do resemble skeletal muscle cells and possess AChRs on their surface membrane. These cells may become antigenic and unleash an autoimmune attack on the muscular endplate AChRs by molecular mimicry.

Answer 17

A rapid diagnosis can be made with the edrophonium (Tensilon) test. This fast-acting acetylcholinesterase inhibitor will cause a transient resolution of symptoms in the myasthenic patient. Repetitive nerve stimulation tests will demonstrate a characteristic decrement of evoked potential amplitude. Antibody tests can confirm the diagnosis and are used to follow treatment response. Eighty percent of patients with general myasthenia have ACh receptor antibodies and 40% of patients without them have antibodies to muscle-specific kinase (anti-MuSK).

Answer 18

Acetylcholinesterase inhibitors (pyridostigmine) are first-line treatment.These medications inhibit the enzyme that degrades ACh (acetylcholinesterase) and allow ACh to build up in the neuromuscular junction. Because of associated thymic abnormalities (thymic hyperplasia or thymoma), thymectomy is a common intervention early in generalized MG. If symptoms persist, immunosuppressive therapy is initiated, primarily with corticosteroids and immunosuppressants.

Answer 19

Myasthenic crisis is a serious complication characterized by severe weakness and respiratory and pharyngeal muscle paresis leading to respiratory failure. It can be spontaneous or occur after an infection or surgical stress.

Answer 20

Early elective intubation Withdrawal of anticholinergic medication Plasmapheresis or intravenous immunoglobulin

Answer 21

Scleroderma is a long term autoimmune disease that results in hardening of the skin. In the more severe form, it also affects internal organs.

Answer 22

``` Localised Scleroderma - only affects the skin - Two types: Linear and Morphoea Systemic Sclerosis - Two types: Limited and Diffuse ```

Answer 23

``` Discoloured oval patches on the skin Can appear anywhere on the body Usually itchy Patches may be hairless and shiny (may improve after a few years and treatment may not be needed) ```

Answer 24

Thickened skin occurs in lines along the face, scalp, legs or arms Occasionally affects underlying bone and muscle May improve after a few years, although can cause permanent growth problems, such as shortened limb

Answer 25

A milder form that only affects skin on the hands, lower arms, feet, lower legs and face, although it can eventually affect the lungs and digestive system too Often starts as Raynaud's phenomenon (a circulation problem where fingers and toes turn white in the cold) other typical symptoms include thickening of the skin over the hands, feet and face, red spots on the skin, hard lumps under the skin, heartburn and problems swallowing (dysphagia) Tends to get gradually worse over time, although it's generally less severe than diffuse systemic sclerosis and can often be controlled with treatment

Answer 26

More likely to affect internal organs Skin changes can affect the whole body Other symptoms can include weight loss, fatigue and joint pain and stiffness Symptoms come on suddenly and get worse quickly over the first few years, but then the condition normally settles and the skin may gradually improve

Answer 27

Physical Examination Blood Tests - ANA by indirect immunofluorescence.

Answer 28

CREST syndrome

Answer 29

This disease most commonly affects women age 30-50 years.

Answer 30

The prevalence of this disease is 240 cases per million people and has been increasing due to earlier detection and longer patient survival after diagnosis.

Answer 31

Symptoms in scleroderma are the result of progressive tissue fibrosis and occlusion of microvasculature resulting from excessive production and deposition of type I and type III collagen from activated fibroblasts.

Answer 32

While the etiology of this pathology is unknown, studies point to a combination of environmental risk factors such as viruses or toxin exposure and genetic factors such as production of Scl-70 antibodies and expression of MHC haplotypes DQ7 and DR2.

Answer 33

``` Viruses Toxin exposure Genetic factors - production of Scl-70 antibodies - expression of MHC haplotypes DQ7 and DR2. ```

Answer 34

Positive ANA by indirect immunofluorescence.

Answer 35

Anti-topoisomerase I (Scl 70) antibody is (about 20% of cases) Anti-RNA polymerase III antibody (about 20% of cases) Anti-centromere antibodies (20% to 25% of cases) The remaining 40% have scleroderma but do not have an as-yet-identified scleroderma-specific autoantibody.

Answer 36

Anti-topoisomerase I (Scl 70) antibody is seen in about 20% of cases and is associated with an increased risk of interstitial lung disease and with diffuse skin involvement

Answer 37

Anti-RNA polymerase III antibody (also about 20% of cases) is associated with renal crisis

Answer 38

Anti-centromere antibodies (20% to 25% of cases) are associated with limited skin involvement and a better overall prognosis

Answer 39

The precise pathophysiology is unknown, but many models have been postulated. Early in the course of the disease, immune system activation, endothelial-cell activation and damage, and fibroblast activation all occur. Selection and activation of a hyper-proliferative fibroblast subpopulation is also implicated. These cells, which produce high levels of collagen, are over-represented in scleroderma.

Answer 40

The activation of the immune system is of paramount importance in the pathogenesis of systemic sclerosis. Antigen-activated T cells promote disease activity by infiltrating the skin and producing pro-fibrotic cytokines. A diverse variety of cytokines is capable of inducing, in vitro, the scleroderma fibroblast phenotype of enhanced proliferation and synthetic function.

Answer 41

Transforming growth factor-beta (TGF-beta) Interleukin-4 (IL-4) Platelet-derived growth factor (PDGF) Connective-tissue growth factor.

Answer 42

Vasculopathy may be linked to TGF-beta and PDGF, and antiendothelial cell autoantibodies.

Answer 43

Treatment of symptoms: - Arthralgias: paracetamol or nonsteroidal antiinflammatory drugs - Myositis: glucocorticoids (first choice), methotrexate, and azathioprine - Pruritus: moisturizers, histamine 1(H1)- and histamine2 (H2)- blockers, tricyclic antidepressants - Pulmonary fibrosis: cyclophosphamide - Raynaud's phenomenon: calcium channel blockers, prazosin, reserpine, or topical nitrates; cervical sympathectomy is reserved for severe cases - Renal hypertension: angiotensin-converting enzyme inhibitors - Skin changes: D-penicillamine or methotrexate

Answer 44

Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes

Answer 45

When pressure is applied to the skin with a sliding motion, the skin rubs off

Answer 46

Pemphigus vulgaris Pemphigus foliaceous Paraneoplastic pemphigus.

Answer 47

Pemphigus vulgaris

Answer 48

Pemphigus is characterized by shallow, painful erosions and blisters that easily rupture with friction or pressure. Mucosal surfaces are also frequently involved

Answer 49

Blisters in pemphigus vulgaris are associated with the binding of IgG autoantibodies to keratinocyte cell surface desmosomal proteins desmoglein 1 and desmoglein 3. These antibodies bind to keratinocyte desmosomes and to desmosome-free areas of the keratinocyte cell membrane. The binding of autoantibodies results in a loss of cell-to-cell adhesion, a process termed acantholysis. The antibody alone is capable of causing blistering without complement or inflammatory cells.

Answer 50

Desmosomes are highly organised intercellular junctions which mediate strong adhesion between cells. In addition to these adhesive functions, desmosomal components are also involved in signal transduction pathways and epidermal organisation

Answer 51

Pathogenic antidesmoglein 1 and antidesmoglein 3 autoantibodies.

Answer 52

Antidesmoglein 3 autoantibodies only

Answer 53

Patients with active disease have circulating and tissue-bound autoantibodies of both the immunoglobulin G1 (IgG1) and immunoglobulin G4 (IgG4) subclasses.

Answer 54

More than 80%

Answer 55

Disease activity correlates with antibody titers in most patients. In patients with pemphigus vulgaris, the presence of antidesmoglein 1 autoantibodies, is more closely correlated with the course of the disease compared with antidesmoglein 3 autoantibodies. Lack of in vivo antibody binding (reversion to a negative result on direct immunofluorescence) is the best indicator of remission and can help predict a lack of flaring when therapy is tapered

Answer 56

To diagnose pemphigus, a skin biopsy must be done to demonstrate anti-desmoglein autoantibodies by direct immunofluorescence on the skin biopsy. These antibodies appear as IgG deposits along the desmosomes between epidermal cells, a pattern reminiscent of chicken wire. Acantholysis may also be seen (individual keratinocytes are detached and free floating). Anti-desmoglein antibodies can also be detected in a blood sample using the ELISA technique. Increased serum levels of antibodies to desmoglein 1 and 3 correlate with disease activity

Answer 57

Treatment of this disease requires oral steroids. Oral steroids must be continued to prevent recurrence of the disease. Other agents such as azathioprine or cyclophosphamide may be used in conjunction with steroids to decrease the steroid dose and lessen the side effects related to high-dose steroids. Mycophenolate mofetil is becoming more widely used as a steroid-sparing agent, but there is limited data supporting its use. In severe cases, plasmapheresis may be required. The lesions should be treated as burns are treated.

Answer 58

Pemphigoid is a rare autoimmune disorder that can develop at any age, but that most often affects the elderly. Pemphigoid is caused by a malfunction of the immune system and results in skin rashes and blistering on the legs, arms, and abdomen

Answer 59

In people aged 60 and older.

Answer 60

The disease is characterized by prodromal erythematous papules that develop into large, tense blisters filled with serous to bloody fluid. The collapsed bullae leave deep erosions and crusts. The condition is often more pruritic than painful, and the mucous membranes are rarely involved. Nikolsky’s sign (separation of the outer layer of the epiderms when lateral pressure is applied to the skin) is negative.

Answer 61

The diagnosis of Bullous pemphigoid is confirmed by immunostaining a skin biopsy specimen. The immunostain in Bullous pemphigoid reveals fluorescence at the dermal-epidermal junction

Answer 62

Pemphigoid produces a split in the cells where the epidermis and the dermis (the layer below the epidermis) meet, causing deep, tense (taut or rigid) blisters that do not break easily. Direct immunofluorescence studies shoe a linear band of immunoglobulin G deposit along the dermal-epidermal junction Pemphigus, on the other hand, causes a separation within the epidermis, and the blisters are soft, limp, and easily broken. Direct immunofluorescence using an anti-IgG antibody shows intercellular IgG deposits in the epidermis and the early intraepidermal vesicle caused by acantholysis.

Answer 63

Autoantibodies are directed against 2 hemidesmosomal proteins, designated BP180 and BP230. Bullous pemphigoid autoantibodies (with the help of complement activation), the infiltration of inflammatory cells, and the release of proteases and various inflammatory mediators, including cytokines, are essential for lesion formation.

Answer 64

Hemidesmosomes are protein complexes that mediate the stable attachement of basal cells to the underlying basement membrane in epithelial tissues, such as the skin. Hemidesmosomes contain at least 5 components which include bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2)

Answer 65

Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced.

Answer 66

The non-collagenous 16A domain that encompasses 76 amino acids and localises directly adjacent to the transmembrane region has been identified as an immunodominant region of the BP180 ectodomain.

Answer 67

BP180NC16A

Answer 68

In most bullous pemphigoid sera, circulating antibodies to BP180NC16A are detected with serum levels correlating with disease activity. Bullous pemphigoid autoantibodies (with the help of complement activation), the infiltration of inflammatory cells, and the release of proteases and various inflammatory mediators, including cytokines, are essential for lesion formation. Studies revealed that antihuman BP180NC16A antibodies and neutrophils are responsible for this tissue injury.

Answer 69

Using an IgG passive transfer approach, there exists in vivo evidence that rabbit antibodies directed against the murine BP180NC16A homologue are pathogenic in mice. These in vitro and in vivo data demonstrate that antibodies specific for the BP180NC16A domain are pathogenic. It is clear that the binding of anti-BP180 antibody to its target is the critical first step in sub-epidermal blister formation in bullous pemphigoid.

Answer 70

Bullous pemphigoid often provokes blood and tissue eosinophilia, which suggests chemoattractants may modulate the eosinophil infiltration. Eotaxin and interleukin (IL)-5 are strongly associated with the tissue eosinophilia of bullous pemphigoid. These findings suggest that eotaxin and IL-5 may be important for eosinophil migration in bullous pemphigoid lesions and that therapies that aim to inhibit production of eotaxin and IL-5 may improve inflammation and blister formation

Answer 71

For mild cases, topical steroids may be used. More severe cases may require systemic steroid therapy. Systemic steroid-sparing agents such as azathioprine, mycophenolate mofetil, cyclophosphamide, or methotrexate may be used in combination with oral prednisone. For patients who are unable to tolerate systemic steroids, azathioprine, dapsone, or tetracycline plus nicotinamide may be used.

Answer 72

Because of the chronic nature of bullous pemphigoid, patients often require long-term use of immunosuppressant agents. Disease recurrence is common