Tolerance Auto-immune Diseases and Tumor Immunity

Aamir Ali Khan
Assistant Professor
Department of Pathology (MLT)

TOLERANCE
Immunological tolerance is the failure to mount an immune
response to an antigen.
 It can be: Natural or "self" tolerance.
This is the failure (Benificial) to attack the body's own proteins
and other antigens.
 If the immune system should respond to "self", an
autoimmune disease may result.

TOLERANCE
Tolerance – a state of unresponsiveness specific for a
given antigen
It is specific (negative) immune response
It is induced by prior exposure to that antigen
Self tolerance – prevents the body to elicit an immune
attack against its own tissues
Mechanisms of active tolerance prevent inflammatory
reactions to many innocuous airborne and food
antigens found at mucosal surfaces

Cont…
Self and non-self discrimination is learned during development
Tolerance is NOT genetically programmed
The time of first encounter is critical in determining responsiveness.
The stage of differentiation of lymphocytes at the time of antigen
confrontation.
The site of encounter.
The nature of cells presenting antigenic epitopes
The number of lymphocytes able to respond
Microenvironment of encounter (expression of cell adhesion
molecules, influence of cytokines etc.)

TOLERANCE PROPERTIES
 Immature or developing lymphocyte is more susceptible to tolerance
induction than mature one.
 Tolerance to foreign antigens is induced even in mature
lymphocytes under special conditions.
 Tolerance of T lymphocytes is a particularly effective for
maintaining long-lived unresponsiveness to self antigens

INHIBITION OF SELF-REACTIVITY
Clonal deletion
Physical elimination of cells from the repertoire during their lifespan
Clonal anergy
Downregulating the intrinsic mechanism of the immune response
such as lack of costimulatory molecules or insufficient second signal for
cell activation
Suppression
Inhibition of cellular activation by interaction with other cells:
(Treg – CD4+, CD25+ T lymphocytes)

MECHANISMS OF TOLERANCE TO SELF-ANTIGENS
Tolerance to self antigen is of two types.
 Central tolerance:
Central tolerance refers to mechanisms of tolerance acting during
lymphocyte development in the thymus or bone marrow.
Experimental studies show that central tolerance is mostly due to the
elimination or inactivation of those T and B cells that recognize self-
antigens.
These cells are destroyed or inactivated after they have expressed receptors
for self-antigens and before they develop into fully immunocompetent
lymphocytes.
Deletion of self-reactive cells at an early stage in their development has
been termed 'clonal abortion' or 'clonal deletion'.

Peripheral tolerance
 Peripheral tolerance refers to mechanisms acting on mature lymphocytes after
they have left the primary lymphoid organs.
 Not all genes are expressed in the thymus so developing T cells cannot be
exposed to all self-antigens.
 Therefore, additional mechanisms for tolerating self- reactive mature T cells
are necessary.
 Mechanisms of peripheral B cell self-tolerance are also necessary because after
stimulation with antigen B cells expand and undergo somatic mutation,
generating a population of B cells with new antigen specificities.
 Some of these cells may be specific for self-antigens.

Introduction
Autoimmune disease definition.
 A disease in which the body produces antibodies that attack its own tissues, leading
to the deterioration and in some cases to the destruction of such tissue.
 An autoimmune disease is a condition arising from an abnormal immune response
to a normal body part.
 There are at least 80 types of autoimmune diseases. Nearly any body part can be
involved.
 Common symptoms include low grade fever and feeling tired. Often symptoms
come and go.
 The cause is generally unknown. Some autoimmune diseases such as lupus run in
families, and certain cases may be triggered by infections or other environmental
factors.

Common auto immune disease
Examples of some common autoimmune disease include
 Celiac disease
 Diabetes mellitus type 1
 Graves disease
 Inflammatory bowel disease
 Multiple sclerosis, psoriasis
 Rheumatoid arthritis
 Systemic lupus erythematosus.

PATHOPHYSIOLOGY
 The human immune system typically produces both T-cells and B-cells that are
capable of being reactive with self-antigens.
 But these self-reactive cells are usually either killed prior to becoming active within
the immune system, placed into a state of anergy (silently removed from their role
within the immune system due to over-activation), or removed from their role within
the immune system by regulatory cells.
 When any one of these mechanisms fail, it is possible to have a reservoir of self-
reactive cells that become functional within the immune system.
 The mechanisms of preventing self-reactive T-cells from being created takes place
through Negative selection process within the thymus as the T-cell is developing
into a mature immune cell.

Rheumatoid arthritis
 Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic
inflammation of the joints. Autoimmune diseases are illnesses that occur when the
body's tissues are mistakenly attacked by their own immune system.
 The immune system contains a complex organization of cells and antibodies
designed normally to "seek and destroy" invaders of the body, particularly
infections.
 Patients with autoimmune diseases have antibodies and immune cells in their blood
that target their own body tissues, where they can be associated with inflammation.
 While inflammation of the tissue around the joints and inflammatory arthritis are
characteristic features of rheumatoid arthritis, the disease can also cause
inflammation and injury in other organs in the body.

Because it can affect multiple
other organs of the body,
rheumatoid arthritis is referred to as
a systemic illness and is sometimes
called rheumatoid disease.
Rheumatoid arthritis is a classic
rheumatic disease. Rheumatoid
arthritis that begins in people under
16 years of age is referred to as
juvenile idiopathic arthritis.

GRAVES DISEASE
Graves' disease, also known as toxic diffuse goiter, is an autoimmune
disease that affects the thyroid.
It frequently results in and is the most common cause of hyperthyroidism. It
also often results in an enlarged thyroid.
It is characterized by an immune response against the thyroid -stimulating
hormone (TSH) receptors present on thyroid cells.
The binding of antibodies of TSH receptors causes continual stimulation of
these receptors resulting in hyperthyroidism

Multiple sclerosis
Multiple sclerosis in which antibodies / T cells are formed against
components of the myelin sheath of the nerve cells. This immunological
attack interferes with the conduction of nerve impulse causing severe and
progressive neurological damage.
It is a demyelinating disease in which the insulating covers of nerve cells in
the brain and spinal cord are damaged.
This damage disrupts the ability of parts of the nervous system to
communicate, resulting in a range of signs and symptoms, including
physical, mental, and sometimes psychiatric problems.
Specific symptoms can include double vision, blindness in one eye, muscle
weakness, trouble with sensation, or trouble with coordination.

THYROIDITIS
Thyroiditis develops from an immune attack against one or more proteins of
the thyroid cells. The destruction of the thyroid gland leads to
hypothyroidism.
Thyroiditis is generally caused by an attack on the thyroid, resulting in
inflammation and damage to the thyroid cells.
This disease is often considered a malfunction of the immune system.
 Antibodies that attack the thyroid are what causes most types of
Thyroiditis.
It can also be caused by an infection, like a virus or bacteria, which works
in the same way as antibodies to cause inflammation in the glands.
Certain people make thyroid antibodies, and Thyroiditis can be considered
an autoimmune disease, because the body acts as if the thyroid gland is
foreign tissue

PERNICIOUS ANEMIA
 Vitamin B12 deficiency anemia, of which pernicious anemia is a type, is a disease
in which not enough red blood cells are present due to a lack of vitamin B12.
 The most common initial symptom is feeling tired, Other symptoms may include
shortness of breath, pale skin, chest pain, numbness in the hands and feet.
 Although pernicious anemia technically refers to cases resulting from not enough
intrinsic factor.
 Lack of intrinsic factor is most commonly due to an autoimmune attack on the cells
that make it in the stomach.

TUMOR ANTIGEN
INTRODUCTION
 Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an
immune response in the host. Tumor antigens are useful tumor markers in
identifying tumor cells with diagnostic tests and are potential candidates for use in
cancer therapy. The field of cancer immunology studies such topics.
 Spontaneously arising human tumors may have new cell surface antigens against
which the host develop both cytophilic antibodies and cellular sensitivity.
Antigen may be of two type .
 A. Tumor associated antigen
 B. Tumor specific transplantation antigen

TUMOR ASSOCIATED ANTIGEN
The significance of tumor associated antigens lie in the fact that these
antigens increase during tumor growth and subsides as the tumor regresses.
During this process the normal antigenic profile of normal cell is lost.
Various new antigens are expressed on the tumor tissues. Virus induced
tumor have normal antigens

TUMOR SPECIFIC TRANSPLANTATION ANTIGEN
 During development of tumor a new antigen that is TSTA (Tumor
Specific Transplantation Antigen) develop on the surface membrane
which is easily accessible to the receptor of effectors and antibody.
 As these tumors possessed antigen that prevented transplantation into
syngenic host and thus called TSTA(Tumor Specific Transplantation
Antigen)

Classification of tumor markers/ Tumor antigens
Tumor Markers are classified as follows:
1. Hormone as tumor Markers
a. Beta-HCG
b. Catecholamine's
c. Calcitonine
Enzymes as tumor Markers
a) ACP
b) ALP
c) CK-BB
Antigens as tumor markers
a. Oncofoetal Antigen
1. AFP
2. CEA
b. Secreted cancer antigen
1. CA-125
2. CA-27.29
3. CA 19-9

HORMONE AS TUMOR MARKERS
1. Calcitonine:
This hormone is used as a marker for modularly carcinoma of
thyroid.
2. Catecholamine:
It is very useful in diagnosis of neuroblastoma and
pheochromocytoma.
3. Beta- HCG:
The Beta unit of Human Chorionic gonadotrophin is normally
produced by placenta.
Elevated beta-HCG levels are most commonly associated with
pregnancy, germ cell tumours and gestational trophoblastic disease

ANTIGENS AS TUMOUR MARKERS
ONCOFOETAL ANTIGENS
S.No Antigen Name Normal value/ location Associated disease
1 Alpha Fetoprotein (AFP) An AFP level of less than 10
ng/mL
Foetal serum/ Undetectable
after birth/ Adult.
Primarily elevated in Hepatocellular carcinoma
and nonseminomatous germ cell tumors.
Elevated level in pregnancy when complicated by a
spinal cord defect.
2 Carcinoembryonic
antigen (CEA)
Normal value: 0-4 ng/ml
Smoker : 0-5ng/ml
Normally synthesized in
embryonic tissue of pancreas,
gut, liver.
Levels are high in adenocarcinoma, especially
colorectal cancer..
Non- neoplastic conditions associated with
elevated CEA levels include cigarette smoking,
peptic ulcer, inflammatory bowel disease,
hypothyroidism, pancreatitis and cirrhosis.
CEA level ordered after malignancy confirmation
and return to normal with 4-6 weeks after
successful surgical resection.

ANTIGENS AS TUMOUR MARKERS
SECRETED ANTIGEN
S.No Antigen Name Normal value/ location Associated disease
1 Cancer antigen 125 Normal value <35U/ml
Normally present in coelomic
epithelium during foetal
development. Which lines the
body cavities and envelopes the
ovaries.
Elevated CA 125 associated with epithelial ovarian
cancer but also increase in other malignancies. Highest
level in tumors with nonmucinous histology.
2 Cancer antigen 19-9 Normal value <37U/ml
Patient with Lewis null blood type
do not produce CA 19-9.
An intracellular adhesion molecule and elevated levels
occur primarily in patient with pancreatic and billiary
tract cancers.
Benign conditions with elevated CA 19-9 levels are
cirrhosis, cholestasis, cholangitis and pancreatitis.
3 Cancer antigen 27.29 Normal value is <38U/ml
Normally present on the apical
surface of the normal epithelium.
Elevated levels associated with Breast cancer.
Benign condition includes liver, kidney and patient
with ovarian cyst
4 Prostate specific antigen
PSA
Normal value is <4ng/ml
Normally produced by prostatic
epithelium.
Highly sensitive in the diagnosis of prostatic cancer.
Benign condition includes prostatic hypertrophy and
prostatic traumas well as after ejaculation.

ENZYME AS TUMOUR MARKERS
ENZYME AS TUMOUR MARKERS
S.No Enzyme Name Normal value/ location Associated disease
1 Acid Phosphatase ACP Normal value is 2ng/ml Association of this enzyme measurement is confirming
the presence of spread of prostatic carcinoma, and in
assisting the response to treatment. The PSA has now
replaced the estimation of ACP in most Laboratories.
2 Neuron specific enolase
NSE
Normal value is Its an isoenzyme of the enzyme Enolase. It is present
in large amount in nerve cells and used to monitor the
treatment of small cell lung cancer.
3 Alkaline phosphatase ALP Normal value is 44 – 147 mg/dl. Increases in primary or secondary liver cancer and also
in secondary bone cancer. ALP is also increased in
lung cancer, GIT cancer, cancer of ovary and
Hodgkin's disease.
4 CPK, 5NTP, Amylase,
Lipase, GGT

Tolerance Auto-immune Diseases and Tumor Immunity

Tolerance Auto-immune Diseases and Tumor Immunity

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