Autoimmune Diseases

Lecture 18

What is autoimmunity by definition?

a specific immune response to self antigens

The following characteristics match what:

• reflects loss of immunologic tolerance to self tissue or cellualr antigens

• characterized by abnormal or excessive activity of self reactive immune effector cells

• can be organ specific, localized, or systemic

• can be mediated by both autoantibodies or by self reactive T lymphocytes

autoimmunty

Most autoimmune diseases tend to be characterized by what?

cyclic periods of alternating clinical disease and convalescence

What are criteria for diganosing an autoimmune disease?

• direct proof: disease can be transferred through cells or autoantibodies

• indirect proof: identifying antigen, isolating homolgoous antigen in animal model, reproducing disease through antigen administration

• isolating self reactive antibodies or t lymphocytes

• circumstantial evidence: familial occurence, lymphocyte infiltrate, MHC association, clinical improvement with immunosuppressive therapy

The development of autoimmunty can be simply described as what?

an escape from the mechanism by which self tolerance is maintained

Immunologic tolerance is maintained by what mechanisms?

• deletion

• anergy

• suppression

What is the process of clonally eliminating self reactive lymphocytes?

deletion / self tolerance

For T lymphocytes, self tolerance occurs as a developmental process of immature lymphocytes in the thymus, termed?

central tolerance

For T lymphocytes, self tolerance occurring as a component of mature effector cells on exposure to antigens in the peripheral tissues is known as?

peripheral tolerance

What is the clonal expansion of those cells capable of self MHC restriction in central tolerance?

positive selection

What is the clonal deletion of those cells expressing TCRs capable of recognizing self antigens in association with MHC molecules on central tolerance?

negative selection

Many self antigens are not present where?

in the thymus or bone marrow

The development of central tolerance requires exposure to what during lymphocyte development?

antigen

Sequestered antigens can be released as a result of infection or trauma and can result in what?

an immunologic response by self reactive lymphocytes

What tissue antigens fall under the sequestered antigen class?

• myelin basic protein

• lens proteins

• sperm protein

Regulation of cellular activation in peripheral tolerance occurs primarily by which three mechanisms?

• anergy

• suppression

• clonal deletion

What is the functional inactivation of lymphocytes that encounter antigen?

anergy

If an antigen presenting cell does not provide the costimulatory signal, the T lymphocyte recevies a negative signal, and what occurs?

the cell becomes anergic

What is the mechanism of peripheral tolerance that occurs through the activation of regualtory cells that prevent immune reactions to self antigens?

suppression

What mechanism of peripheral tolerance has two possible outcomes including lymphocyte proliferation and cell death?

clonal deletion

If the antigen in immunologically priveleged sites are released as the result of trauma or infection, they have the potential to cause a severe immune response as a consequence of what?

activating self reactive lymphocytes

Post traumatic uveitis and orchitis are thought to be the result of teh relase of what?

sequestered antigens

What are immune priveleged sites?

• testis

• eye

• brain

What are the three mechanisms of autoimmunuity?

• failure of central tolerance

• failure of peripheral tolerance

• genetic factors in autoimmunity

In autoimmune diseases, antigen persistence is though in part to occur through what?

epitope spreading

What is the process by which the immune response spreads from one epitope of an antigenic molecule to another, non-cross reacting, epitope of the same antigenic molecules, or from one epitope of different peptides that are a part of a large complex?

epitope spreading

What is the predominant autoantibody in systemic lupus erythematous?

antinuclear antibosy (ANA)

The causes of SLE remains undetermined, although the presence of autoantibodies directed against a number of tissues and cellular components suggests that the underlying immunologic abnormality is what?

a failure to maintain self tolerance

What are common clinical findings of SLE in dogs?

• fever

• nonerosive polyarthritis

• glomerulonephritis

• mucocutaneous lesions

• lymph node and splenic enlargement

• hemoatologic abnormalities such as anemia, thrombocytopenia, and leukopenia

The renal lesion associated with SLE is the result of what?

immune complex deposition

The majority os lesions in SLE are the result of what?

immune complex disease (type III hypersensitivity)

What are the four distinct disorders included in inflammatory myopathies?

• masticatory muscle myositis

• generalized inflammatory myositis

• dermatomyositis

• extraocular myositis

What is most often seen as a component of an underlying systemic disease process or as an adverse reaction to drug or vaccine administration?

vasculitis

What is vasculitis?

inflammation of the walls of blood vessels

Vasculitis is what type of hypersensitivity reaction?

type III

What is the idiopathic febrile disease characterized by a systemic necrotizing vasculitis that occurs primarily in young beagle dogs and is suspected to be immune mediated?

juvenile polyarthritis (beagle pain syndrome)

What are clinical signs of beagle pain syndrome (juvenile polyarthritis)?

• febrile (104F-107F)

• young dog (4-10 months)

• anorexia

• hunched stance

• cervical pain

• unwillingness to move head and neck

• leukocytosis with neutrophilia, nonregnerative anemia, and hypoalbuminema

• CSF anaylsis: neutrophilic pleocytosis with mild to moderate increases in micro protein

What lesions are associated with beagle pain syndrome (juvenile polyarthritis)?

severe necrotizing vasculitis and perivasculitis with thrombosis of small to medium sized blood vessels in the leptomeninges of the cervical spinal cord, cranial mediastinum, and heart