3. An endogenous immune response
to endogenous antigen
A loss of tolerance to self antigen
4. Review the mechanisms of immunologic
tolerance
Discuss the pathogenesis of
autoimmune diseases
Identify therapeutic approaches to
autoimmunity
5. A state in which the individual is incapable
of developing an immune response
to a specific antigen
Refers to a lack of response to an
individual’s antigens, underlying our ability
to live in harmony with our own cells
and tissues
7. • clonal deletion of autoreactive T
and B lymphocytes during their
maturation in the central lymphoid
organs
Central
• self-reactive T cells that escape
intrathymic negative selection can
inflict tissue injury unless these are
deleted in the peripheral tissues
Peripheral
10. Lymphoid precursor
Immature lymphocytes
Apoptosis
(Deletion)
Change in receptors
(receptor editing ; B
Cell)
Development
of regulatory
T Lymphocytes
(CD4+ T Cells only)
Recognition of Self Antigen
Mature lymphocytes
Recognition of Self Antigen
Apoptosis
(Deletion)
Anergy Suppression
CENTRAL
TOLERANCE
PERIPHERAL
TOLERANCE
18. T cells can suppress immune responses of
both
T and B cells, either directly or by production
of cytokines (TGF-beta and IL-10)
19. Recognition of self
antigen in thymus
Regulatory T Cells
Recognition of self
antigen in peripheral
tissues
Inhibition of T Cell Activation
Inhibition of T Cell
Effector Functions
Thymus Lymph Node
20. IMMUNE RESPONSE :
EXPRESSION OF ANTI-APOPTOPIC (SURVIVAL) PROTEINS
APC
Naïve
T Cell
IL-2
Anti-apoptopic
protein
T Cell Proliferation
& Differentiation
25. ACTIVATION OF ANTIGEN PRESENTING CELLS
Microbe
Activation
of APC
Presentation of
antigen by
APC
Self
antigen
B7 CD28 Self tissue
AUTOIMMUNITY
26. Result from loss of tolerance to self
antigens
T cell or antibody-mediated mechanisms
of tissue injury
Tolerance of self reactive T cells is important
for prevention of autoimmune diseases
32. • Autoimmunity runs in families
• Pattern of inheritance is multigenci
• HLA alleles associated with specific autoimmune
responses and diseases
Genetic
• Estrogen promotes autoimmunity
• Females more often affected
Hormonal
• Infections
• Drug-induced autoimmunity
Environmental
36. Molecular mimicry
Release of sequestered self antigens
Escape of autoreactive clones
Imbalance of suppressor- helper
T cell function
Polyclonal lymphocyte activation
38. MOLECULAR MIMICRY BETWEEN PROTEINS OF INFECTIOUS ORGANISMS
AND HUMAN HOST PROTEINS
PROTEIN RESIDUE SEQUENCE
Human cytomegalovirus IE2
HLA-DR molecule
79
60
P D P L G R P D E D
V T E L G R P D A E
Poliovirus VP2
Acetylcholine receptor
70
176
S T T K E S R G T T
T V I K E S R G T K
Papilloma virus E2
Insulin receptor
76
66
S L H L E S L K D S
V Y G L E S L K D L
Rabies virus glycoprotein
Insulin receptor
147
764
T K E S L V I I S
N K E S L V I S E
Klebsiella pneumoniae nitrogenase
HLA-B27 molecule
186
70
S R Q T D R E D E
K A Q T D R E D L
39. MOLECULAR MIMICRY BETWEEN PROTEINS OF INFECTIOUS ORGANISMS
AND HUMAN HOST PROTEINS
PROTEIN RESIDUE SEQUENCE
Adenovirus 12 E1B
α-Gliadin
384
206
L R R G M F R P S Q C N
L G Q G S F R P S Q Q N
Human immunodeficiency virus p24
Human IgG constant region
160
466
G V E T T T P S
G V E T T T P S
Measles virus P3
Corticotropin
13
18
L E C I R A L K
L E C I R A C K
Measles virus P3
Myelin basic protein
31
61
E I S D N L G Q E
E I S F K L G Q E
42. Trauma to one eye results in the
release of sequestered intraocular
protein antigens
Released intraocular antigen is
carried to lymph nodes and
activates T Cells
43. Effector T Cells return via
bloodstream and encounter antigen
in both eyes
44. Anatomic alterations
Inflammation, ischemic injury, trauma
Exposure of self antigens that are normally
concealed from the immune system
Intraocular proteins & sperm
Hormonal influences
Autoimmune diseases: females > males
SLE
45.
46. Autoantibodies against self components
Antigen-antibody immune complexes deposit in organs
Autoreactive T cells against self-components
Combinations of above
47. OPSONIZATION AND PHAGOCYTOSIS
Opsonized Cell
Complement
Activation
Phagocyte
C3
b
C3b
receptor
Phagocytosed Cell
PHAGOCYTOSIS
Autoimmune hemolytic anemia
Autoimmune thrombocytopenic purpura
Hemolysis in transfusion reactions
48. Antibody
deposition
Antigen in
extracellular matrix
Complement and Fc
receptor mediated
recruitment &
activation of
inflammatory cells
MECHANISM OF
ANTIBODY
DEPOSITION
EFFECTOR
MECHANISMS OF
TISSUE INJURY
Neutrophils and
Macrophages
Enzymes,
reactive
oxygen species
Tissue
injury
49. COMPLEMENT AND FC RECEPTOR-MEDIATED
INFLAMMATION
Complement
Activation
Neutrophil
Activation
Complement
by-products
(C5, C3a)
Ab mediated glomerulonephritis
Fc
R
INFLAMMATION
& TISSUE INJURY
51. Circulating
immune complexes
Site of deposition
of immune
complexes
Complement and Fc
receptor mediated
recruitment &
activation of
inflammatory cells
VASCULITIS
Neutrophil
granule enzymes,
reactive oxygen species
Neutrophils
Blood
Vessel
54. Nature of complexes
Small complexes deposited in vessels
Large complexes are cleared by phagocytes
Characteristics of blood vessels
Capillaries in renal glomeruli & synovia
Plasma ultrafiltered at high hydrostatic pressure
High blood flow, high volume of mediators
& cytokines
59. IgE Antibodies attach
to the IgE receptors
Normal Activation
of Mast Cell
Mast Cell
Antigen attaches to the
IgE in cross-linkage
Activating Degranulation
60. IgE Antibodies attach
to the IgE receptors
In Chronic
Autoimmune Urticaria
Mast Cell
Auto IgG attaches
to the IgE
Activating Degranulation
Auto IgG attaches
to the IgE receptor
or
65. An endogenous immune response
to endogenous antigen
A loss of tolerance to self antigen
66. Molecular mimicry
Release of sequestered self antigens
Escape of autoreactive clones
Imbalance of suppressor- helper
T cell function
Polyclonal lymphocyte activation
67. Autoantibodies against self components
Antigen-antibody immune complexes deposit in organs
Autoreactive T cells against self-components
Combinations of above
Autoimmunity is the failure of the normal mechanisms of self-tolerance that results in reactions against one’s own cells and tissues
Review the mechanisms of immunologic tolerance
Discuss the pathogenesis of autoimmune diseases
Identify therapeutic approaches to the treatment of autoimmunity
During their maturation in the thymus, many immature T cells that recognize self antigens with high avidity are deleted.
T cell activation
T cell responses are induced when the cells recognize an antigen presented by a professional APC and activating receptors on the T cells such as CD28 recognize costimulators on the APCs such as B7.
APCs are required for T cell activation
Purified CD4 T cells do not respond to a protein antigen by itself but do respond to the antigen in the presence of APCs.
The function of the APCs is to display peptides derived from the antigen to T cells. APCs also express costimulators that are important for T cell activation.
Functions of costimulation in T cell activation
The resting APC expresses few or no costimulators and fails to activate naïve T cells.
Microbes and cytokines produced during innante immune responses activate the APCs to express costimulators, such as B7 molecules. The APCs then become capable of activating naïve T cells. Activated APCs also produce cytokines such as IL-12 which stimulate the differentiation of naïve T cells into effector cells.
Mechanisms of T cell anergy
If the T cell recognizes a self antigen without costimulation, the T cell becomes unresponsive to the antigen because of a block in signalling from the TCR complex, or engagement of inhibitory receptors.
The signaling block may be the result of recruitment of phosphatases to the TCR complex, or the activation of ubiquitin ligases that degrade signaling proteins. Regardless of the mechanism, the T cell remains viable, but is unable to respond to the self antigen.
Suppression of self-reactive lymphocytes by regulatory T cells
Regulatory T lymphocytes are a subset of CD4 T cells whose function is to suppress immune responses and maintain self tolerance.
Regulatory T cells are generated mainly by self antigen recognition in the thymus, but they also develop in peripheral lymphoid organs.
The majority of these CD4 regulatory T lymphocytes express high levels of the IL-2 receptor α chain but not other markers of inflammation.
The generation and survival of regulatory T cells are dependent on the cytokines TGF β and IL-2 and costimulation by the B7:CD28 pathyway.
In response to immunogenic antigens and growth factors, lymphocytes express anti-apoptotic proteins that promote their survival and allow immune responses to develop.
T cells that recognize self antigens without costimulation or an accompanying immune response may activate a pro-apoptotic protein called bim, resulting in apoptosis by the mitochondrial pathway.
Repeated stimulation of T cells results in the co-expression of death receptors and their ligands and engagement of the death receptors triggers apoptotic death.
In CD4 T cells, the relevant death receptor is called Fas (CD95) and its ligand is Fas ligand (FasL).
Fas is a member of the TNF receptor family (TNF) and FasL is homologous to the cytokine TNF.
When T cells are repeatedly activated, FasL is expressed on the cell surface, and it binds to surface Fas on the same or adjacent T cells. This activates a cascade of intracellular cysteine proteases, called caspases, which ultimately cause the apoptotic death of the cells.
Self – nonself discrimination is the ability of the immune system to recognize and respond to foreign antigens but not to self antigens.
Self – nonself discrimination is the ability of the immune system to recognize and respond to foreign antigens but not to self antigens.
Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the self reactive T cells are activated rather than rendered tolerant.
Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the self reactive T cells are activated rather than rendered tolerant.
Various genetic loci may confer susceptibility to autoimmunity, in part by influencing the maintenance of self tolerance. Environmental triggers such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in tissue injury.
Various genetic loci may confer susceptibility to autoimmunity, in part by influencing the maintenance of self tolerance. Environmental triggers such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of self-reactive T cells, resulting in tissue injury.
Among the genes associated with autoimmunity, the strongest associations are with MHC genes, especially class II MHC genes.
HLA typing of large groups of patients with various autoimmune diseases has shown that some HLA alleles occur at higher frequency in these patients than in the general population.
The strongest such association is between ankylosing spondylitis, an inflammatory, presumable autoimmune disease of vertebral joints, and the class I HLA allele B27. Individuals who are HLA-B27 positive have a 90-100 fold greater chance for developing ankylosing spondylitis than do individuals lacking B27.
Infectious microbes may contain antigens that cross-react with self antigens, so immune responses to the microbes may result in reactions against self antigens.
This phenomenon is called molecular mimicry because the antigens of the microbe cross-react with or mimic, self antigens.
Molecular sequencing has revealed numerous short stretches of homologies between viruses and different receptors.
The significance of limited homologies between microbial and self antigens remains to be established and it has been difficult to prove that a microbial protein can actually cause a disease that resembles a spontaneous autoimmune disease.
Anatomic alterations in tissues, caused by inflammation, ischemic injury or trauma, may lead to the exposure of self antigens that are normally concealed from the immune system.
Hormonal influences play a role in some autoimmune diseases.
Many autoimmune diseases have a higher incidence in females than in males. For instance SLE affects women about 10 times more frequently than men.
Many autoimmune diseases have a higher incidence in females than in males. For instance SLE affects women about 10 times more frequently than men.
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.
First, antibodies may directly opsonize cells, or they may activate the complement system, resulting in the production of complement proteins that opsonize cells. These cells are phagocytosed and destroyed by phagocytes that express receptors for the Fc portions of antibodies and receptors for complement proteins. This is the principal mechanism of cell destruction in autoimmue hemolytic anemia and autoimmune trhomocytopenic purpura.
Second, antibodies deposited in tissues recruit neutrophils and macrophages, which bind to the antibodies or attached complement proteins by Fc and complement receptors. These leukocytes are activated and their products induce acute inflammation and tissue injuries. This is the mechanism of injury in antibody-mediated glomerulonephritis.
Antibodies recruit leukocytes by binding to Fc receptors or by activating complement and thereby releasing by-products that are chemotactic for leukocytes.
Antigen-antibody complexes are produced during normal immune responses, but they cause disease only when they are produced in excessive amounts, are not efficiently cleared, and become deposited in the tissues.
Antigen-antibody complexes are produced during normal immune responses, but they cause disease only when they are produced in excessive amounts, are not efficiently cleared, and become deposited in the tissues.
The amount of immune complex deposition in tissues is determined by the nature of the complexes and the characteristics of the blood vessels.
Small complexes are often not phagocytosed and tend to be depostied in large vessels more than large complexes, which are usually cleared by phagocytes.
Complexes containing cationic antigens bind avidly to negatively charged components of the basement membranes of blood vessels and kidney glomeruli. Such complexes typically produced severe and long-lasting tissue injury.
Capillaries in the renal glomeruli and synovia are vessels in which plasma is ultrafiltered by passing through the capillary wall at high hydrostatic pressure, and these locations are among the most common sites of immune complex deposition.
Third, antibodies that bind to normal cellular receptors or other proteins may interfere with the functions of these receptors or proteins and cause diseases without inflammation or tissue damage.
The pituitary gland secretes thyroid stimulating hormone (TSH) which acts on the thyroid to induce release of thyroid hormones.
Thyroid hormones act on the pituitary to shut down production of TSH, suppressing further thyroid hormone synthesis.
Autoimmune B cells makes antibodies against TSH receptor that also stimulate thyroid hormone production.
Thyroid hormones shut down TSH production but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production.
Production of thyroid hormones is regulated by thyroid-stimulating hormones (TSH)
The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of two thyroid hormones: thyroxine and triiodothyronine
A person with Grave’s Disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the thyroid
The auto-antibodies are called long-acting thyroid stimulating hormones
Even there is inhibition of TSH, the hormone synthesis is still stimulated
Autoimmunity is the failure of the normal mechanisms of self-tolerance that results in reactions against one’s own cells and tissues
