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Clinical Immunology and Biochemistry > Autoimmune Diseases > Flashcards

Autoimmune Diseases Flashcards

1
Q

What is tolerance?

A

Tolerance refers to the specific immunological non reactivity to an antigen resulting from a previous exposure to the same antigen.

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2
Q

What is the most important form of tolerance?

A

The most important form of tolerance is non-reactivity to self antigens.

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3
Q

What did early observations of tolerance show?

A

Grafts between different individuals of the same species (allografts or homografts) were rejected unless they were between identical twins (isografts)

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4
Q

What are autografts

A

Autografts involve the transplantation of tissues (usually skin) from one part of the body to another in the same individual. Such grafts are not rejected because no foreign antigens are involved.

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5
Q

What are isografts?

A

Grafts between identical twins

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6
Q

Why are autografts not rejected?

A

Because the are no foreign antigens involved

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7
Q

Describe the neonatal tolerance experiment

A

In 1953, Peter Medawar and his colleagues induced immunological tolerance to skin allografts in mice by foetal and neonatal injection of allogenic cells (grafts that are genetically non identical but are from same species)

The hypothesis was that “mammals and birds never develop, or develop to only a limited degree, the power to react immunologically against foreign homologous tissue cells to which they have been exposed sufficiently early in foetal life’’

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8
Q

What are the mechanisms of tolerance induction?

A

The exact mechanism of induction and maintenance of tolerance is not fully understood, but involves:

Central Tolerance:

  • positive and negative selection of T cells
  • clonal deletion of self reactive cells

Peripheral tolerance

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9
Q

What is the function of AIRE?

A

AIRE (autoimmune regulator) is a transcription factor that turns on the expression of peripheral self antigen genes in the thymus

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10
Q

What occurs in AIRE defective patients?

A

AIRE gene defective patients develop a rare form of autoimmunity that destroys multiple endocrine organs

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11
Q

What is the function of peripheral tolerance?

A

The clonal deletion is not a foolproof system and often T and B cells fail to undergo deletion and therefore such cells can potentially cause autoimmune disease once they reach the peripheral lymphoid organs.

The immune system has devised several additional check points so that tolerance can be maintained.

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12
Q

When is peripheral tolerance developed?

A

Peripheral tolerance is developed after T and B cells mature and enter the periphery.

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13
Q

By what mechanisms is peripheral tolerance maintained?

A

The generation of hyporesponsiveness (anergy) or deletion of lymphocytes which encounter antigen in the absence of the co-stimulatory signals that accompany inflammation

The suppression of autoreactive cells by ‘regulatory’ T cells

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14
Q

What is autoimmunity?

A

The breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self.

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15
Q

What are the causes (etiology) of autoimmune diseases?

A

The exact etiology of most autoimmune diseases is not known. However, various theories have been offered.

These include:

Activation of autoreactive clones
Loss of suppressor cells
Cross reactive antigens including exogenous antigens (pathogens) and altered self antigens (chemical and viral infections)
Release of sequestered antigens

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16
Q

What are the mechanisms of activation of autoreactive clones?

A

The negative selection in the thymus may not be fully functional to eliminate self reactive cells.

Not all self antigens may be represented in the thymus or certain antigens may not be properly processed and presented

T cells with low affinity for self antigen can become activated if they encounter an activated dendritic cell presenting that antigen and expressing high levels of co-stimulatory molecules or proinflammatory cytokines as a result of infection

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17
Q

What is required for T-cell activation?

A

T cells require two signals to become fully activated (co-stimulation).

A first signal, which is antigen-specific, is provided through the T cell receptor which interacts with peptide-MHC molecules on the membrane of antigen presenting cells.

A second signal, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of APC and the T cell

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18
Q

What are cross reactive antigens?

A

Antigens on certain pathogens may have determinants which cross react with self antigens and an immune response against these determinants may lead to effector cell or antibodies against tissue antigens.

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19
Q

Give examples of autoimmune diseases caused by cross-reactive antigens

A

Rheumatic fever
Anticardiolipin antibodies during syphilis
Association between Klebsiella and ankylosing spondylitis

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20
Q

What can occur on the release of sequestered antigens?

A

Some antigens in immunologically privileged sites(e.g. in brain, testes, eye) induce a tolerogenic response when they interact with T cells.

Also a locally immunosuppressive environment in these tissues and other active mechanisms prevent or limit immune responses in these sites.

If barriers are breached (e.g. trauma) the newly exposed antigen can activate these tolerant T cells which can then attack the organ containing the antigen.

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21
Q

What is direct evidence of autoimmunity?

A

Direct evidence requires transmissibility of the characteristic lesions of the disease from human to human, or human to animal.

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22
Q

Give examples of direct evidence of autoimmunity

A

In which there are temporary signs of disease in the infant due to transplacental transfer:

  • Idiopathic thrombocytopenic purpura
  • Graves’ disease
  • Myasthenia gravis

Where the disease can be transmitted from humans to animals by autoantibody:

  • Pemphigus vulgaris
  • Bullous pemphigoid
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23
Q

How can autoimmunity be demonstrated in vitro?

A

Inhibition of the fixation of vitamin B12 by intrinsic factor can be produced by autoantibodies from certain patients with pernicious anemia, and overproduction of thyroid hormones can be produced by autoantibodies from patients with Graves’ disease.

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24
Q

What is indirect evidence of autoimmunity?

A

Indirect evidence requires re-creation of the human disease in an animal model. The majority of autoimmune diseases fit in this category.

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25
Q

Give examples of indirect evidence of autoimmunity

A

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

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26
Q

What is myasthenia gravis?

A

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

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27
Q

What are the symptoms of myasthenia gravis?

A

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.

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28
Q

When is Myasthenia Gravis most commonly seen?

A

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

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29
Q

What does an injection of edrophonium cause in a patient with Myasthenia Gravis?

A

Injection of edrophonium causes a transient resolution of symptoms.

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30
Q

What is Myasthenia Gravis associated with?

A

It is associated with other autoimmune disorders and hyperthyroidism.

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31
Q

What is the differential diagnosis for Myasthenia Gravis?

A

Lambert-Eaton myasthenic syndrome (LEMS)

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32
Q

What is Lambert-Eaton myasthenic syndrome (LEMS)?

A

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

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33
Q

How do autoantibodies cause Myasthenia Gravis?

A

Blocking ACh receptors

Degrading ACh receptors

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34
Q

What is edrophonium?

A

Short acting acetylcholinesterase inhibitor

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35
Q

Describe the pathophysiology of Myasthenia Gravis

A

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.

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36
Q

What causes the fatigability seen in Myasthenia Gravis?

A

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.

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37
Q

How much do the number of AChRs need to reduce by for a patient with Myasthenia Gravis to become symptomatic?

A

30%

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38
Q

What are the mechanisms for Myasthenia Gravis?

A

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

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39
Q

What is seronegative Myasthenia Gravis?

A

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

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40
Q

What causes seronegative Myasthenia Gravis?

A

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

41
Q

What is the role of the thymus in the pathogenesis of Myasthenia Gravis?

A

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.

42
Q

How many patients with Myasthenia Gravis have some degree of thymus abnormality?

A

75%

43
Q

How can Myasthenia Gravis be diagnosed?

A

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).

44
Q

How can Myasthenia Gravis be treated?

A

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.

45
Q

What is Myasthenic Crisis?

A

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.

46
Q

How is Myasthenic Crisis treated?

A

Early elective intubation
Withdrawal of anticholinergic medication
Plasmapheresis or intravenous immunoglobulin

47
Q

What is Scleroderma?

A

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

48
Q

What are the types of Scleroderma?

A 
Localised Scleroderma
 - only affects the skin
 - Two types: Linear and Morphoea 
Systemic Sclerosis
 - Two types: Limited and Diffuse
49
Q

What are the symptoms of Localised Morphoea?

A 
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)
50
Q

What are the symptoms of Localised Linear Scleroderma?

A

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

51
Q

What are the symptoms of Limited Systemic Sclerosis?

A

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

52
Q

What are the symptoms of Diffuse Systemic Sclerosis?

A

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

53
Q

How is Scleroderma diagnosed?

A

Physical Examination
Blood Tests
- ANA by indirect immunofluorescence.

54
Q

What are the limited symptoms of scleroderma known as?

A

CREST syndrome

55
Q

Who is scleroderma most common in?

A

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

56
Q

What is the prevalence of Scleroderma?

A

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.

57
Q

Describe the pathogenesis of scleroderma

A

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.

58
Q

What causes scleroderma?

A

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.

59
Q

What are the risk factors associated with Scleroderma?

A 
Viruses
Toxin exposure 
Genetic factors 
 - production of Scl-70 antibodies
 - expression of MHC haplotypes DQ7 and DR2.
60
Q

What is seen in 90% of scleroderma patients?

A

Positive ANA by indirect immunofluorescence.

61
Q

What antibodies are associated with scleroderma?

A

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.

62
Q

What is Scl 70 antibody associated with?

A

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

63
Q

What is Anti-RNA polymerase III antibody associated with?

A

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

64
Q

What are Anti-centromere antibodies associated with?

A

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

65
Q

Describe the pathophysiology of scleroderma

A

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.

66
Q

How does the activation of the immune system affect sclerosis?

A

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.

67
Q

What profibrotic cytokines cause fibrosis in scleroderma?

A

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

68
Q

What causes vasculopathy in scleroderma?

A

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

69
Q

How is scleroderma managed?

A

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
70
Q

What is pemphigus?

A

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

71
Q

What is Nikolsky’s sign?

A

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

72
Q

What are the different types of pemphigus?

A

Pemphigus vulgaris
Pemphigus foliaceous
Paraneoplastic pemphigus.

73
Q

What is the most common form of pemphigus?

A

Pemphigus vulgaris

74
Q

How is pemphigus characterised?

A

Pemphigus is characterized by shallow, painful erosions and blisters that easily rupture with friction or pressure.

Mucosal surfaces are also frequently involved

75
Q

Describe the pathophysiology of pemphigus

A

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.

76
Q

What are desmosomes?

A

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

77
Q

What autoantibodies are seen in the mucocutaneous form of pemphigus vulgaris?

A

Pathogenic antidesmoglein 1 and antidesmoglein 3 autoantibodies.

78
Q

What autoantibodies are seen in the mucosal form of pemphigus vulgaris?

A

Antidesmoglein 3 autoantibodies only

79
Q

What autoantibodies to patients with active pemphigus vulgaris have?

A

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

80
Q

How many patients with active pemphigus produce autoantibodies to desmoglein?

A

More than 80%

81
Q

Describe the correlation between autoantibodies and disease activity in patients with pemphigus

A

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

82
Q

How is pemphigus diagnosed?

A

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

83
Q

How is pemphigus treated?

A

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.

84
Q

What is pemphigoid?

A

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

85
Q

When is pemphigoid most commonly seen?

A

In people aged 60 and older.

86
Q

What are the symptoms of pemphigoid?

A

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.

87
Q

How is pemphigoid diagnosed?

A

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

88
Q

What is the difference between pemphigus and pemphigoid?

A

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.

89
Q

Describe the pathophysiology of pemphigoid

A

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.

90
Q

What are hemidesmosomes?

A

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)

91
Q

What is immunodominance?

A

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

92
Q

Which part of the BP180 protein in the hemidesmosomes is most immunodominant?

A

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.

93
Q

Which autoantibody is thought to be responsible for bullous pemphigoid?

A

BP180NC16A

94
Q

What is the function of BP180NC16A in Bullous Pemphigoid?

A

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.

95
Q

What evidence is there to show that antibodies against BP180 cause pemphigoid?

A

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.

96
Q

Why does eosinophilia occur in bullous pemphigoid?

A

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

97
Q

How is bullous pemphigoid treated?

A

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.

98
Q

Is bullous pemphigoid chronic or acute?

A

Chronic

99
Q

How does the course of bullous pemphigoid progress?

A

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

Disease recurrence is common

Clinical Immunology and Biochemistry (14 decks)

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