Immunological Tolerance and Autoimmunity
Lymphocytes of a normal individual are tolerant of individual’s own antigens (self-antigens). It’s important to
understand this concept in order to comprehend autoimmunity
T cell Tolerance
- Central T cell tolerance (positive and negative selection)
 During their maturation in the thymus, certain immature T cells are deleted by central T cell tolerance
o Immature T cells that do not recognize self antigen
o Immature T cells with high affinity for self antigen
- Peripheral T cell tolerance
 Because the thymus lacks peripheral self antigens, immature T cells of the thymus do not become
tolerance to these antigens
 Mechanisms of peripheral T cell tolerance prevent T cells from reacting with peripheral self antigens
 Utilize three mechanisms
o Clonal Anergy
 Functional inactivation of T cells
 Induced when T cells recognize antigens (signal 1) without adequate level of
costimulation (B7 and CD28, signal 2)
 Because resident APCs of a peripheral tissue are constantly presenting self antigens
without costimulatory signals, T cells that recognize and respond these antigens must
be eliminated via clonal anergy
o Deletion
 Deletion of T cells via apoptitic cell death occurs via two mechanisms
- Antigen recognition without costimulation
 T cells that recognize self antigens without costimulation become
anergic and undergo apoptosis via activation of pro-apoptitic protein
- Activation-induced cell death
 Repeated stimulation of T cells by self antigens triggers pathways of
apoptosis that result in elimination of continuously self-reactive T cells
 Repeated activation of T cells leads to expression of Fas (CD95) and
Fas ligand (FasL) on surface of T cells
 FasL binds to Fas on the same or neighboring cell and
signaling through Fas induces apoptitic death of the cell
expressing it. Therefore, Fas is considered the death receptor
o Suppression of T cells
 T-regulatory cells (Tregs) play a crucial role in suppressing self-reactive T cells
- Though some immature T cells that recognize self-antigens with high affinity
die by apoptosis, a subset of these T cells are selected further as Tregs
 Tregs are CD4+ cells and develop in the thymus
- Tregs constitutively express CD25 (IL-2 receptor) at high levels, unlike other
naïve CD4+ cells that express CD25 only after antigen stimulation
 Induction of Treg suppressive activity requires antigenic stimulation (i.e. activation
signal via TCR)
 Suppression in non-antigen specific and induced by Treg immunosuppressive
cytokines TGFβ and IL-10
- These cytokines can suppress a wide range of immune responses via
“bystander suppression”
- Cytokines inhibit activity of both lymphocytes and APCs
B cell Tolerance
- Central B cell tolerance
 During B cell maturation in bone marrow, immature B cells that recognize self antigens with high
affinity are dealt with by central B cell tolerance via two mechanisms
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Deletion
Change in receptor specificity (editing)
 Via production of new antibody light chain (heavy chain remains the same)
 If editing fails to eliminate autoreactivity, the immature B cell will be deleted
 Weaker recognition of self antigen may lead to anergy rather than cell death
Peripheral B cell tolerance
 If mature B cells that recognize self antigens in peripheral tissues do not receive help from T cells
(because Th cell are absent or tolerant), three mechanisms are utilized
o Anergy
o Die by apoptosis
o B cells are excluded from migrating to lymphoid follicles
Failure of self-tolerance results in immune reactions against self-antigens, or autoimmune reactions
Tolerance to an Allogeneic Fetus
- Except in instances where the mother and father are syngeneic, the mammalian fetus expresses paternallyinherited antigens that are allogeneic to the mother
- Allogeneic fetus is not normally rejected
- Protection of fetus against maternal immunity is not completely understood, but involves several mechanisms
 IDO
o Fetal placental tissue (trophoblast) invades the uterus and secretes enzyme that catalbolizes
trypophan, indolamine 2,3-dioxygenase (IDO)
o Trypophan is an essential amino acid for rapidly dividing cells, so IDO inhibits alloreactive T
cell proliferation
o Inhibition of IDO function by IDO-inhibiting drug, 1-methyl-trypophan, induces abortions in
mice (rejection of allogeneic fetuses)
 HLA-G
o Trophoblast cells do not express MHC molecules, making them targets for NK cells
o Expression of non-polymorphic HLA (i.e. HLA-G) inhibits killing by NK cells
 HLA-G binds to inhibitory receptors on NK cells
 Crry
o Trophoblast cell express high levels of C3 and C4 inhibitor, Crry (complement receptor 1related protein y), making them resistant to complement-mediated damage
o Crry-deficient embryos die before birth and show evidence of complement activation
 FasL
o Trophoblast tissue can directly kill aggressive maternal lymphocytes
o Trophoblasts cells express FasL (Fas ligand), which causes apoptosis of activated maternal
lympohocytes expressing Fas
o In mice lacking functional FasL, pregnancy is associated with extensive leukocyte infiltrates
and necrosis at the decidual-placental interface leading to fetal resorption and small litters
 Tregs
o Tregs (CD4+CD25+ T cells) are necessary for the maternal immune system to tolerate paternal
alloantigens expressed by the fetus
o Tregs increase in number during pregnancy – about 30% of Th cells of the uterus are Tregs
o Absence of CD25+ cells leads to a failure of gestation due to immunological fetal rejection
Etiology of Autoimmunity
- Though understanding etiology of autoimmune disorders is limited, several general concepts have emerged
- Increased expression of costimulators by tissue APCs
 An infection of a tissue (microbes) may induce a local innate immune response that can lead to
increased expression of costimulators (B7) and cytokines by tissue APCs
 Activated APCS then activate self-reactive T cells that encounter self antigens within the tissue
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Polyclonal lymphocyte activators
 Many autoantibody-caused diseases are thought to occur due to failure of B cell tolerances
 Exposure to B cell mitogens (i.e. bacterial LPS) activates a large number of B cells, including those
that are specific for self antigens
o B cells produce IgM antibodies with low affinity (as they are produced without T cell help)
 Polyclonal lymphocyte activation may occur via stimulation of autoreactive T cells by bacterial
superantigens
Exposure to hidden (sequestered) antigens of immunologically-privileged sites
 Certain self antigens are sequestered anatomically from the immune system, are not seen by developing
lymphocytes, and therefore do not induce self-tolerance
o Antigens of the CNS, eye, testes
 Exposure of mature T cells to these hidden antigens following tissue injury (i.e. trauma, infection) can
lead to autoimmune reactions (Example – autoantibodies to sperm after vasectomy)
o Posttraumatic uveitis and orchitis are diseases thought to be due to autoimmune responses
Genetic Factors
 Strongest evidence for existence of genetic component to autoimmune disease is the higher incidence
of disease in twins (monozygotic more so than dizygotic) and family members when compared to an
unrelated population
 Most autoimmune disorders are multigenic, where affected individuals inherit multiple genetic
polymorphisms that contribute to disease susceptibility
 MHC genes are strongly associated with autoimmunity
 Specific autoimmune diseases occur more commonly in dogs with certain DLA alleles
o Diabetes mellitus is associated with DLA-A3, DLA-A7, DLA-A10, DLA-B4
o SLE (due to deficiency of C3, a non-MHC molecule) is associated with DLA-A7
Molecular mimicry
 Sharing of epitopes between an infectious agent and a self antigen
 Infection of such a pathogen can lead to activation of autoreactive lymphocytes
o Parasite Trypanosoma cruzi contains antigens that share antigenic identity with mammalian
neurons and cardiac muscle and autoantibodies cause CNS disorders and heart disease
o Antigenic identity exists between equine eye antigens and those of Leptospira interrogans,
therefore leptospiral infections have been associated with equine recurrent uveitis
Hormonal factors
 Many autoimmune disorders have a higher incidence in females than males
o Estrogen is considered to be immunostimulatory
o Females tend to mount more pro-inflammatory Th1 responses
Role of Th17 Cells in Autoimmunity
- Until recently, Th1 cells were thought to exclusively drive cell-mediated autoimmune tissue damage
- It has now been established that Th17 cells also play an important role in autoimmunity
 Mice deficient in IL-17 (cytokine of Th17 cells) develop experimental autoimmune encephalomyelitis
(EAE) with delayed onset and diminished severity
 Increased expression of IL-17 is seen in multiple sclerosis and rheumatoid arthritis
Autoimmune Diseases
- Lymphocytic thyroiditis
 Affects dogs and chickens
 Autoantibodies against thyroid proteins (i.e. thyroglobulin) interfere with iodine uptake and lead to
decreased production of thyroid hormones (hypothyroidism)
 Affected thyroids are severely infiltrated with macrophages, plasma cells, and lymphocytes
 Clinical signs congruent with those of hypothyroidism – overweight, inactivity, hair loss, infertility
- Hyperthyroidism
 Most commonly occurs in older cats
 Typically caused by adenomatous hyperplasia – the presence of an increased number of thyroid
hormone-producing cells within the thyroid gland
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In cats, hyperplasia is almost always benign (only 3-5% of hyperthyroid cats have cancerous
thyroid growth)
o Clinical signs associated with increased metabolic rate – weight loss
 Although hyperthyroidism is typically caused by thyroid hyperplasia, the disease is also found to be
immunologically-mediated
o Infiltration of the thyroid gland by lymphocytes
o Autoantibodies to thyroid peroxidase (TPO) have a hypothyroid effect, one that may be
dominated by the hyperthyroid effect of the hyperplasia
Autoimmune adrenalitis
 Hypoadrenocortical function due to autoimmune destruction of the adrenal cortex
 Lymphocyte infiltration of the cortex and its subsequent destruction lead to reduced synthesis and
secretion of mineralcorticoids
Equine recurrent uveitis
 Most common cause of blindness in horses
 Due to antigenic identity (mimicry) between equine eye antigens and antigen of Leptospira interrogans
Epidermolysis bullosa acquisita
 Skin disease of the Great Dane
 Affected animals develop IgA and IgG autoantibodies specific for type VII collagen against anchoring
fibrils of the basement membrane
 Accumulation of neutrophils within the superficial dermis, resulting in microabscess formation
 Characterized by oral ulceration, necrosis, bacterial infection, cutaneous sloughing
Alopecia areata
 Reported in humans, primates, dogs, cats, horses, cattle
 Autoimmune disease directed against cells in hair follicles
 Follicles in affected areas have a perifollicular and bulbar lymphocyte infiltrate
o In dogs, lesions are infiltrated by IgG antibodies, CD4+, CD8+, and Langerhans cells
 Targets of immunological attack may be bulbar keratinocytes or hair follicle keratins
Treatment of Autoimmune Diseases
- Treatments of autoimmune diseases reduce immune activation and its harmful consequences. A future goal of
the therapy is to block activity specificity of those T cells that are specific to self antigens
- Drugs
 In some organ-specific diseases, metabolic control drugs are usually sufficient
o Use of insulin in the treatment of T1D
o Use of thyroid hormones in the treatment of hypothyroidism
 Immunosuppressive drugs slow proliferation of lymphocytes (but place patient at higher risk of
infection)
o Corticosteroids, azathioprine, cyclophosphamide, methotrexate
o Corticosteroids control inflammation and the influx of neutrophils and other phagocytes
- Plasmapheresis
 Plasma exchange is used to reduce circulating levels of autoantibodies and immune-complexes
 Patients with myasthenia gravis, rheumatoid arthritis, and SLE experience short-term benefit from
plasmapheresis
- Monoclonal antibody treatment
 Anti-TNFα MAb is used is treatment of rheumatoid arthritis