Transcript T Cell Mediated Disease

#40 Immune-Mediated Diseases and
Autoimmunity I
Immunology 297
September 4, 2015
Ikuo Tsunoda, MD, PhD
Department of Microbiology and Immunology
LSUHSC, Shreveport
Homepage: http://tsunodalaboratory.web.fc2.com/
E-mail: [email protected]
12-4 Autoimmune Diseases: General Principles
 Autoimmune disease
 A disease in which the primary mechanism
of pathology is an immune attack directed
against components of the self
 Autoantigen
 A self component that is the target of the
immune response in an autoimmune
disease
 Systemic versus Organ-specific autoimmunity
Figure 13‐5. Types of autoimmunity.
Autoimmunity occurs when the
protective mechanisms of self-tolerance
fail or are bypassed; pathologic
reactions against self-antigens may
result. Anti-self antibodies and selfreacting cells disrupt tissues and cause
organ damage, or autoimmune disease.
Two major categories.
1) Organ-specific: typified by thyroiditis
and myasthenia gravis, attack is
directed against a single antigen in a
single organ or tissue.
2) Non–organ-specific: target
widespread self-antigens such as
nucleic acids in systemic lupus
erythematosus. Organ damage is widely
disseminated owing to the ubiquitous
distribution of the antigen, and immune
complex deposition may cause remote
systemic injury.
The organ-specific diseases occur
together with greater than expected
likelihood. For example, 5% to 10% of
patients with myasthenia gravis also
have antibody-mediated thyroid
disease. Disease clustering also occurs
at the other end of the spectrum, with
frequent overlap between, for example,
dermatomyositis and other
rheumatologic syndromes.
7.5 million patients in the US (National Psoriasis Foundation)
http://www.psoriasis.org/
Autoantigen unknown, IL-17 blockade effective
Autoimmunity is the result of
genetic susceptibility and
environmental trigger?
Identical twin studies: If one twin develop
an autoimmune disease, 10-50% of the
other twin develop the disease
Some HLA alleles occur at higher
frequency in autoimmune disease patients
than in the general population
Multiple polymorphisms (variants) in nonHLA genes associated with autoimmune
disease susceptibility: CTLA4, PTPN22,
CD25 (IL-2 receptor α chain), IL-23R
Single-gene defects cause autoimmunity:
FAS/FasL (ALPS), AIRE (APS), FOXP3
(IPEX), complement genes (lupus-like
disease)
Susceptibility loci for autoimmune diseases. The chromosomal loci associated with some autoimmune diseases are shown. The
location of candidate genes of immunologic interest are indicated as ovals on the left of the chromosomes. These ovals are color
coded to indicate the diseases to which the genes are linked. SLE, systemic lupus erythematosus; AITD, autoimmune thyroid
disease; RA, rheumatoid arthritis; T1D, type 1 diabetes. PTPN22, protein tyrosine phosphatase (Yamada R and K Ymamoto. Recent
findings on genes associated with inflammatory diseases. Mutation Research 573:136-151, )
p arm
centromere
q arm
Genetic loci implicated as risk factors for the development of SLE, MS, RA, and
IDDM in humans. CTLA4 is located at 2q33. CTLA4 gene polymorphism
associated with type 1 diabetes, autoimmune thyroiditis, Graves’ disease
Treg
Figure 13‐4. Mechanisms of selftolerance. Tolerance relies on the talent
of self-recognition that B cells and T cells
probably acquire during maturation.
Lymphocytes unable to recognize self or
lacking the willingness to tolerate self are
deleted or rendered anergic. These
mechanisms are sequestration, lack of
anergy,
antigen presentation, clonal energy,
clonal deletion, and suppressor cells. In
sequestration (1) some tissue proteins
(eg, myelin basic protein, lens of the eye)
are anatomically isolated from exposure
to lymphocytes; anatomic barriers (eg,
the blood–brain barrier) preclude contact
with T cells. In lack of antigen
presentation (2), some tissues contain
cells lacking the capability of antigenpresenting cells (APCs)—cells unable to
express major histocompatibility complex
(MHC). Neurons, for example, cannot
express MHC. In clonal anergy (3), T-cell
activation requires a secondary costimulatory signal received by the CD28
complex. If a T cell confronts an antigen
on a cell that lacks a functional B7
protein, the T cell becomes inactivated or
tolerant. In clonal deletion (4), during
maturation, T cells must demonstrate
recognition of self and tolerance of self.
This takes place in the thymus (Th). T-cell
lines failing to pass these tests are
deleted or inactivated. Regulatory T cells
(5) (Treg) and other cells have been
proposed to induce self-tolerance.
sequestration
Immunologically privileged
sites (brain, etc)
Release of Sequestered Antigens
 Some self-antigens are sequestered in specialized tissues
and cannot be expressed in the thymus or bone marrow.
 These are not seen by the developing immune system –
will not induce self-tolerance.
 Exposure of T cells to these normally sequestered/tissuespecific self-antigens in the periphery results in their
activation.
Examples of Sequestered Antigens
 Central nervous system (CNS)
antigens, such as myelin
oligodendrocyte glycoprotein (MOG),
associated with multiple sclerosis (MS)
 Lens and corneal proteins of the eye
following infection or trauma
•
Tissue grafts
placed in these
sites do not elicit
immune
responses
•
No conventional
lymphatics
•
Surrounded by
tissue barriers,
e.g. blood-brain
barrier
Immunopathology of autoimmune diseases
 Effector mechanisms
 Damage by cytotoxic IgG antibody (type
II), immune complex (type III) or T cellmediated inflammation (type IV)
 Induction (sensitization) of autoimmune
responses
 Molecular mimicry
 Epitope spreading
Immune pathology of autoimmune diseases
 Effector mechanisms
 Damage by cytotoxic IgG antibody (type
II), immune complex (type III) or T cellmediated inflammation (type IV)
 Induction (sensitization) of autoimmune
responses
 Molecular mimicry
 Epitope spreading
Table 18-1. Classification of Immunological Diseases
Type of
hypersensitivity
Pathologic immune
mechanisms
Mechanisms of tissue injury and
disease
Immediate
IgE antibody
hypersensitivity:
Type I
Antibody mediated: IgM, IgG antibodies
Type II
against cell surface or
extracellular matrix
antigens
Mast cells and their mediators (vasoactive
amines, lipid mediators, cytokines)
Immune complex
mediated: Type III
Complement- and Fc receptor-mediated
recruitment and activation of leukocytes
T cell mediated:
Type IV
Immune complexes of
circulating antigens and
IgM or IgG antibodies
1. CD4+ T cells (delayedtype hypersensitivity)
2. CD8+ CTLs (T cellmediated cytolysis)
Opsonization and phagocytosis of cells
Complement- and Fc receptor-mediated
recruitment and activation of leukocytes
(neutrophils, macrophages)
Abnormalities in cellular functions, e.g.,
hormone receptor signaling
1. Macrophage activation, cytokinemediated inflammation
2. Direct target cell killing, cytokinemediated inflammation
Hypersensitivity reaction
•Allergy; reaction against environmental antigens (allergen), food pollen, house dust
•Autoimmunity; reaction against self-antigens (autoantigen)
Type II
Type III
Types of
antibodymediated
diseases.
Antibodies may
bind specifically to
tissue antigens
(A), or they may
be deposited as
immune
complexes that
are formed in the
circulation (B). In
both cases, the
deposited
antibodies induce
inflammation,
leading to tissue
injury.
Effector mechanisms of
antibody-mediated disease.
A.Antibodies opsonize cells and may
activate complement, generating
complement products that also
opsonize cells, leading to
phagocytosis of the cells through
phagocyte Fc receptors or C3
receptors.
B.Antibodies recruit leukocytes by
binding to Fc receptors or by
activating complement and thereby
releasing by-products that are
chemotactic for leukocytes.
C.Antibodies specific for cell surface
receptors for hormones or
neurotransmitters may stimulate the
activity of the receptors even in the
absence of the hormone (left panel)
or may inhibit binding of the
neurotransmitter to its receptor (right
panel). TSH, thyroid-stimulating
hormone.
12-5 Antibody-mediated
autoimmune diseases
• Autoantibody binds to targets, leading to
damage by Fc receptor+ macrophage and/or
complement lysis (type II hypersensitivity-type)
 Autoimmune hemolytic anemia (antibody against red
blood cells)
 Autoimmune thrombocytic purpura (antibody against
platelets)
 Goodpasture’s syndrome (antibody against collagen
type IV in the kidney and lung basement membrane)
• Immune complex formation and deposition,
activating phagocytes and causing damage
(type III hypersensitivity-type)
 Systemic lupus erythematosus
• Direct effect of autoantibodies on the
autoantigen affecting its important function
 Pemphigus vulgaris
 Myasthenia gravis
http://missinglink.ucsf.edu/lm/dermatologyglossary/pemphigus_vulgaris.html
Myasthenia gravis (MG)
•Autoimmune disease of the postsynaptic
neuromuscular junction
•200 cases per million
•Weakness and fatigability
•Acetylcholine receptor antibodies in 85%
•Thymic hyperplasia in 65%
•Thymoma in 15%
•Treatment: cholinesterase inhibitors for
symptom control, immunosuppressive therapy,
thymectomy, plasma exchange
Myasthenia gravis (MG)
• MG: Latin. Gravis =grave. Greek. mys, muscle, + astheneia, weakness]
severe muscle weakness
• Acetylcholine (ACh) receptor in the neuromuscular junction receives
Ach from motor neurons to induce muscle contraction
• In MG, autoantibody reacts with the ACh receptor
• Autoantibody induces the internalization of receptors and can also
block the binding of Ach, and block receptor function and prevent
muscle contraction
Figure 13‐24. Neuromuscular junction in myasthenia gravis. A, The normal neuromuscular junction
releases acetylcholine from presynaptic vesicles that bind to acetylcholine receptors at the apices of
postsynaptic junctional folds. Bound acetylcholine receptors allow sodium influx, which causes
depolarization of postsynaptic membranes. Acetylcholine is degraded by acetylcholinesterase,
located deep within the postsynaptic crypts. B, Acetylcholine receptor antibodies bind to
acetylcholine receptors, causing accelerated endocytosis and degradation of receptors, blockade of
acetylcholine binding sites, and complement-mediated damage to the postsynaptic membrane. The
density of acetylcholine receptors is reduced, and the remaining receptors are blocked by the
presence of bound antibody. Postsynaptic junctional folds are flattened, damaged, and disorganized
by this complement-mediated attack. The reduced population of receptor disallows sufficient
membrane depolarization to originate a propagating muscle membrane action potential.
Systemic
circulation
Thymus
Cortex
Medulla
Cortical thymic epithelial cell Medullary thymic epithelial cell (mTEC)
AIRE
MHC
MHC
CCL19
CCL21
autoantigen
TCR
CD4
CD4T
tissue
specific
autoantigen
RANKL,CD40L
Mediated mTEC
proliferation
CD8
CCR7 expression
RANKL,CD40L expression
DP
Cell death
Positive selection
CD4SP
S1P1 expressionCD8T
CD8SP
Systemic
circulation
Negative
selection
Cell death or nTreg generation
Dendritic cell
Foxp3
nTreg
Myasthenia gravis:
CHRNA1 gene (encoding Ach receptor α subunit) polymorphism?
AIRE modulates CHRNA1 expression level?
Treg abnormality?
Graves’ disease
Basedow’s disease
• Autoimmune disease in which autoantibodies
react with the receptor for thyroid-stimulating
hormone (TSH) and activate it
• Hyperthyroidism: thyroid cells continually
secrete thyroid hormones
• Hyperactivity, sweating, fatigue, weight loss
with increased appetite, tachycardia, atrial
fibrillation (President George HW Bush),
exophthalmos(eye protrusion, Barbara Bush)
(“Millie” the Bushes' dog has lupus)
• Graves' disease occurs in up to 2% of women
• Typically occurs between 20 and 50 years of
age, but it also occurs in the elderly
http://www.accessmedicine.com/content.aspx?aID=2877433
Harrison’s Internal Medicine
Graves’ Ophthalmopathy (GO)
•In addition to hyperthyroidism,
over 25–50% of individuals
with Graves’ disease have
clinical involvement of the
eyes known as thyroidassociated ophthalmopathy
(TAO) or GO
Prabhakar, B. S. et al. Endocr Rev 2003;24:802-835
Current Perspective on the Pathogenesis of Graves’ Disease
and Ophthalmopathy
FIG. 2. Patient with severe GO
Copyright ©2003 The Endocrine Society
•3–5% of patients suffer from
intense pain and inflammation
with double vision or even loss
of vision
•GO can be explained by an
increase in the volume of both
the orbital fatty connective
tissues and the extraocular
muscle bodies
Gail Devers, Olympian
Masako Natsume, Actress
Missy
Elliott,
rapper
Barbara
Bush, first
lady
•
•
Thyroid hormones regulate basal
metabolism and body temperature
Thyroid hormones T4 and T3 feed
back to inhibit hypothalamic
production of thyrotropin-releasing
hormone (TRH) and pituitary
production of thyroid-stimulating
hormone (TSH). TSH stimulates
thyroid gland production of T4 and
T3. Right. Thyroid follicles are
formed by thyroid epithelial cells
surrounding proteinaceous colloid,
which contains thyroglobulin.
Follicular cells, which are polarized,
synthesize thyroglobulin and carry
out thyroid hormone biosynthesis.
TSH-R, thyroid-stimulating hormone
receptor; Tg, thyroglobulin; NIS,
sodium-iodide symporter; TPO,
thyroid peroxidase; DIT,
diiodotyrosine; MIT,
monoiodotyrosine.
Hyperthyroidism in
Graves’ disease
• Thyroid stimulating hormone
(TSH) from the pituitary
gland acts on thyroid cells
through the TSH receptor to
stimulate the release of
thyroid hormones
• Thyroid hormones
negatively regulate TSH
production
• In Graves’ disease, TSH
receptor antibodies act like
TSH to stimulate cells to
secrete thyroid hormones
• This secretion is
unregulated, since the
antibodies are always
present
Autoimmune thyroiditis
(Hashimoto’s thyroiditis)
• Reported by Dr. Hakaru Hashimoto
• Autoimmune hypothyroidism
• Tiredness, weakness, feeling cold,
weight gain with poor appetite
• CD4+, CD8+ T cells and B cells
infiltrate in the thyroid
• CD8+ cytotoxic T cells mediated
thyroid cell destruction
• Local cytokine production, TNF, IL1, IFN-γ
• Autoantibody
• HLA-DR3, 4, 5, CTLA-4
Puffy eyes, thickened, pale skin
Pathologic features of
antibody-mediated
glomerulonephritis.
A.Glomerulonephritis induced
by an antibody against the
glomerular basement membrane
(Goodpasture's syndrome): the
light micrograph shows
glomerular inflammation and
severe damage, and
immunofluorescence shows
smooth (linear) deposits of
antibody along the basement
membrane.
normal glomerulus
B.Glomerulonephritis induced
by the deposition of immune
complexes (SLE): the light
micrograph shows neutrophilic
inflammation, and the
immunofluorescence and
electron micrograph show
coarse (granular) deposits of
antigen-antibody complexes
along the basement membrane.
T Cell-Mediated Diseases
• T cells may cause disease...
 in response to persistent antigens
 Delayed-type hypersensitivity
 in response to self antigens
 Autoimmunity
APC,
antigenpresenting
cell
Mechanisms of T cell-mediated diseases. A. In delayed-type hypersensitivity
reactions, CD4+ T cells (and sometimes CD8+ cells) respond to tissue antigens by
secreting cytokines that stimulate inflammation and activate phagocytes, leading to
tissue injury. B. In some diseases, CD8+ CTLs directly kill tissue cells
A) Perivascular mononuclear cell
(lymphocyte and macrophage)
infiltrates in the dermis.
B) B) Immunohistochemistry
demonstrate CD4+ T cells
DTH reaction is manifested by induration with redness and swelling at
the site of the challenge, which peaks at 48 hours
13-0 Overview: Causes and nature of
hypersensitivity reactions
• Type IV hypersensitivity is cell-mediated, usually
by Th1 cells, less often by cytotoxic T cells
• Known as delayed-type hypersensitivity (DTH),
because local exposure to antigen must be
followed by migration of antigen specific T cells
into the site
• In many cases, the sensitizing antigen is a small
molecule (hapten, such as poison ivy, nickel)
covalently attached to proteins (haptenation)
• Most DTH is elicited by haptenated proteins,
although some antigens may bind directly to
MHC molecules
13-5 Delayed-type
hypersensitivity reactions
• In most cases the proteins that
become haptenated to produce
DTH are extracellular, which bind
to MHC class II
• Lipids-soluble antigens can cross
the cell membrane and haptenate
cytoplasmic proteins, bind to MHC
class I molecule
• Contact dermatitis
 Poison ivy, nickel (in jewelry)
• Celiac disease
Delayed-type Hypersensitivity
The sensitization (induction) phase
occurs during the first exposure to an
antigen. It results in the clonal
expansion of antigen-specific T
cells as well as the maturation
of both effector and memory cells.
The effector phase involves the
localization of effector T cells
to the site of antigen deposition
and their subsequent production
of specific cytokines that direct
the actions of other cell types.
Poison Ivy Reaction
Antigenic compound in urushiol is a small
hydrophobic molecule, pentadecacatechol
Urushiol
Urushi (Japanese) = lacquer
Blistering skin lesions
on hand of patient with
poison ivy contact
dermatitis
Autoimmune Diseases due to
Type IV Hypersensitivity
Abbas et al: Cellular and Molecular Immunology Updated 6E Self-assessment
Which one of the following statement concerning
autoimmune disease is true?
A) Autoimmunity manifests as organ-specific, not systemic, disease
B) Infectious microorganisms are frequently present in autoimmune lesions.
C) Effector mechanisms in autoimmunity include circulating autoantibodies,
immune complexes, and autoreactive T lymphocytes.
D) Among the genes associated with autoimmunity, associations are
particularly prevalent with class I MHC genes.
E) Many autoimmune diseases show higher incidence in males than in
females.
Explanation: Various effector mechanisms are responsible for tissue injury in different
autoimmune diseases. These include circulating autoantibodies, immune complexes,
and autoreactive T lymphocytes. Autoimmune diseases may be either systemic (i.e.,
systemic lupus erythematosus) or organ specific (i.e., type 1 diabetes mellitus, multiple
sclerosis). Among the genes associated with autoimmunity, the strongest associations
are with MHC genes and usually with class II MHC genes (ankylosing spondylitis is an
exception). In most cases of autoimmunity, infectious microorganisms are neither
present in lesions nor detectable in patients when autoimmunity develops; this
suggests that lesions in autoimmunity result not from the infectious agent directly but
from host immune responses that may be triggered by microbes. Finally, many
autoimmune diseases show higher incidence in females than in males, although the
reasons for this are not well understood.