18. Diseases of Immunity: Autoimmune Diseases

most often occurs as the result of the development of antibodies directed against antigens on the surface of a cell or in a tissue, with the result that the cell or tissue is destroyed

type II cytotoxic hypersensitivity

The antigens in a type II cytotoxic hypersensitivity may be either ________ or _________.

endogenous; exogenous

What is the pathogenesis of many immune mediated and autoimmune diseases centered on?

the development of antireceptor or anti-surface antigen antibodies and a type II hypersensitivity reaction

The largest group of cytotoxic hypersensitivity reactions involves what diseases? What are antibodies directed against?

hematologic diseases; antigens present on the surface of red blood cells and platelets

The majority of cytotoxic type II diseases result in what?

decrease or loss of a population of cells

The physical and biochemical properties of red blood cells, platelets, and leukocytes makes them susceptible to what?

cytotoxic reactions

What are the two properties of red blood cells that make them uniquely susceptible to being involved in type II reactions?

1. S

2. B

1. surface contains a complex array of blood group antigens that can become targets of antibody responses, as is commonly the cause in transfusion reactions or immune-mediated hemolytic disease of the newborn

2. biochemical properties of RBCs make them prone to adsorb substances such as drugs or antigenic components of infectious agents or tumors

In autoimmune forms of hemolytic anemia, agranulocytosis, and thrombocytopenia, there is a breakdown of ________ and the subsequent ________ of ________ to normal cells, and as a result, they are ________.

tolerance; development; antibodies; destroyed

reaction that occurs through the formation of antigen-antibody complexes that activate complement and result in tissue damage

type III immune complex hypersensitivity

In a type III immune complex hypersensitivity reaction, why is the cell or tissue being destroyed?

immune complexes either become stuck to that cell or are deposited in that tissue

True or false: The targeted tissue is not a direct target of the immune response. The pathogenesis begins with the formation of immune complexes that become lodged or are formed in or deposited in tissue and are capable of activating the complement system.

true

Similarly to type II hypersensitivity reactions, type III reactions most frequently involve what? When do they occur?

IgM and IgG; within hours after exposure in a sensitized host

True or false: Antigen-antibody complexes form as a part of a normal immune response and usually facilitate the clearance of antigen by the phagocytic system without resulting in a type III hypersensitivity reaction.

true

What is the most important factor that determines whether a type III reaction will occur or not?

the relationship of the antibody response to the quantity of antigen

What happens when the antibody is in great excess of antigen?

the antigen-antibody complexes formed are large and insoluble and easily removed by the phagocytic system

What happens when the antigen is in great excess of the quantity of antibody?

the antigen-antibody complexes formed are too small to be capable of becoming lodged in tissues or of activating the complement system

What happens when antigen is in slight excess of the antibody?

these small soluble complexes can become lodged in tissue and activate the complement system

What tissues are particularly vulnerable to deposition of immune complexes?

B
S
G
C

• blood vessels

• synovial membranes

• glomeruli

• choroid plexus

What is a type IV delayed type hypersensitivity reaction the result of? What is the resulting immune response mediated by?

activation of sensitized T lymphocytes to a specific antigen; either direct cytotoxicity by lymphocytes or by the release of cytokines that act primarily through macrophages to produce chronic inflammation

True or false: Type IV hypersensitivity is also known as cell-mediated hypersensitivity because it is the result of the interaction of T lymphocytes and the specific antigen to which they have been sensitized. The resulting immune response produces chronic inflammatory reactions. Because these responses are dependent on sensitized T lymphocytes and require 24-48 hours to develop, they are also referred to as delayed-type hypersensitivity (DTH).

true

Unlike type I, II, and III, what is type IV hypersensitivity not dependent on?

an antibody

What is type IV delayed type hypersensitivity the underlying pathogenesis for?

allergic contact hypersensitivity and granulomatous inflammatory responses

Type IV delayed type hypersensitivity frequently occur in response to what? What do they cause? What are these diseases characterized by? What do they typically result in and why?

intracellular organisms; cause extensive tissue damage; granulomatous inflammation; host is unable to destroy or eliminate the organism, resulting in antigen persistence

What does granulomatous inflammation designate? What else may there be concurrently?

that the inflammatory infiltrate has specific attributes, notably the presence of morphologically transformed macrophages into epithelial-like cells commonly called epithelioid macrophages; many multinucleated giant cells that represent fused macrophages and may become organized into granulomas

What is the body trying to do in type IV delayed type hypersensitivity?

limit the spread or wall off the inciting antigen

What is the prototypical DTH reaction?

localized tuberculin response

specific immune response to self-antigens that reflects a loss of immunologic tolerance to self-tissue or cellular antigens and is characterized by abnormal or excessive activity of self-reactive immune effector cells that can be organ specific, localized, or systemic and can be mediated by both autoantibodies and by self-reactive T lmyphocytes

autoimmunity

What do most autoimmune diseases tend to be characterized by?

cyclic periods of alternating clinical disease and convalescence

What may criteria for diagnosing an autoimmune disease include?

D
I
I
C

• direct proof

• indirect proof

• isolating self-reactive antibodies or T lymphocytes

• circumstantial evidence

How can the development of autoimmunity be simply described?

as an escape from the mechanism by which self-tolerance is maintained

How is tolerance maintained?

D
A
S

• deletion

• anergy

• suppression

process of clonally eliminating self-reactive lymphocytes

deletion or self-tolerance

developmental process of immature lymphocytes in the thymus for T lymphocytes

central tolerance

component of mature effector cells on exposure to antigen in the peripheral tissues

peripheral tolerance

in central tolerance, this is the clonal expansion of those cells capable of self-MHC restriction

positive restriction

in central tolerance, this is the clonal deletion of those cells expressing TCRs capable of recognizing self-antigens in association with MHC molecules

negative selection

What does the development of central tolerance require?

exposure to the antigen during lymphocyte development

Where are many self-antigens not present?

in the thymus or bone marrow

What are these self-antigens commonly referred to as? What are examples?

M
L
S

sequestered antigens

• myelin basic protein

• lens proteins

• sperm protein

What can these antigens be released as a result of? What do they result in?

infection or trauma; immunologic response by self reactive lymphocytes

What are the mechanisms for the regulation of cellular activation in peripheral tolerance?

A
S
C

• anergy

• suppression

• clonal deletion

functional inactivation of lymphocytes that encounter antigen

anergy

How will a cell become anergic?

if an antigen-presenting cell (APC) does not provide the costimulatory signal, the T lymphocyte receives a negative signal

How does the anergy of B lymphocytes largely occur?

through the absence of specific TH lymphocyte activation

this mechanism of peripheral tolerance occurs through the activation of regulatory cells that prevent immune reactions to self-antigens

suppression by regulatory T lymphocytes

Antigens that are not expressed in the thymus or are “cryptic” in nature have the potential to induce what?

a self-reactive immune response

What are examples of immunologically privileged sites? Why are they termed this?

T
E
B

• testis

• eye

• brain

because of the difficulty in eliciting an immune response to the antigens in these tissues

What happens to antigens in immunologically privileged sites?

cannot be seen by the immune system because they are sequestered

True or false: If the antigens in these tissues are released as the result of trauma or infection, they have the potential to cause a severe immune response as a consequence of activating self-reactive lymphocytes. Posttraumatic uveitis and orchitis are thought to be the result of the release of sequestered antigens.

true

What are the mechanisms of autoimmunity?

F
F
G

• failure of central tolerance

• failure of peripheral tolerance

• genetic factors in autoimmunity

Once an autoimmune disease is initiated, the clinical course is generally ________ and characterized by ________ periods of ________ and ________.

progressive; cyclic; exacerbation; remission

What is required to maintain the functional immune response?

antigen persistence

In autoimmune diseases, how is antigen persistence thought in part to occur?

through epitope spreading

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

epitope spreading

Autoimmune diseases can be ________ ________ or ________.

organ specific; systemic

With many of the organ-specific diseases, what is suspected? Why?

immunologically mediated pathogenesis; because of the finding of a lymphocytic inflammatory reaction within the affected tissue

________, autoantibodies may be identified in the circulation.

rarely

one of the most well-studied systemic autoimmune diseases in human beings and is characterized by the production of autoantibodies directed against a wide array of normal tissue and cellular components

systemic lupus erythematosus

What is the predominant autoantibody in SLE? What is it directed against?

antinuclear antibody (ANA); nuclear antigens

True or false: As with many autoimmune diseases, SLE has a highly variable and often progressive clinical course characterized by a variety of clinical and immunologic abnormalities. There is no clear sex predilection in domestic species. There are certain breeds of dogs that have a higher incidence. The average age of diagnosis is approximately 5 years.

true

While the cause of SLE remains undetermined, what is the underlying immunologic abnormality thought to be?

failure to maintain self-tolerance

What are found in high percentages in patients with SLE?

ANAs

What are the common clinical findings in dogs with SLE? What are the most common immunologic finding?

F
N
G
M
L
H

• fever

• nonerosive polyarthritis

• glomerulonephritis

• mucocutaneous lesions

• lymph node and splenic enlargement

• hematologic abnormalities (anemia, thrombocytopenia, and leukopenia)

ANAs

What is the most common finding lesion associated with SLE?

polyarthritis

characterized as a nonerosive lesion that commonly affects the intervertebral, carpal, tarsal, and temporomandibular joints

polyarthritis in SLE

What is the primary differential diagnosis for the arthritis? What type of lesion is this?

rheumatoid arthritis; erosive

In SLE, what is the renal lesion the result of?

immune complex deposition

True or false: In SLE, skin lesions are highly variable and nonspecific in canine SLE. The face, ears, and digital extremities are frequently involved and characterized by erythema, ulceration, and exfoliative dermatitis. In the cat, SLE is less well recognized and manifests with fever, glomerulonephritis, dermatitis, and hemolytic anemia. The ANA test in cats is less reliable because many normal cats can have positive test results. Horses with SLE similarly present with generalized skin disease and may also have glomerulonephritis, arthritis, and hemolytic anemia.

true

What is the majority of the lesions in SLE the result of?

immune complex disease (type III hypersensitivity)

uncommon, heterogenous group of disorders that are characterized by skeletal muscle damage and inflammation and an immune mediated pathogen is suspected

inflammatory myopathies

What 4 distinct disorders are considered inflammatory myopathies?

M
G
D
E

• masticatory muscle myositis

• generalized inflammatory myositis

• dermatomyositis

• extraocular myositis

inflammatory disease of the skin, muscles, and vasculature affecting primarily young dogs and the cause and pathogenesis is unknown

dermatomyositis

inflammation of the walls of the blood vessels

vasculitis

Vasculitis is most often seen as a component of an ________ ________ disease process or as an _________ ________ to drug or vaccine adminsitration.

underlying systemic; adverse reaction

What does the pathogenesis of vasculitis involve?

type III hypersensitivity reaction with the formation of immune complexes that are either formed in the vessel wall or formed in the circulation and lodge in the vessel wall

True or false: The inflammation of the blood vessel is not the result of an immunologic response to components of the blood vessel but rather an innocent bystander phenomenon with the formation or deposition of complexes in the wall and then activation of the complement system.

true

idiopathic febrile disease characterized by a systemic necrotizing vasculitis that occurs primarily in young beagle dogs and is suspected to be immune mediated, based on clinical signs, immunologic abnormalities, and pathologic findings

beagle pain syndrome

What is the classic presentation of beagle pain syndrome?

F
A
H
C
U

• febrile young dogs

• anorexia

• hunched stance

• cervical pain

• unwillingness to move the head and neck