Tolerance Auto-immune Diseases and Tumor Immunity

Aamir Ali Khan

Assistant Professor

Department of Pathology (MLT)

TOLERANCEImmunological 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 responseIt is induced by prior exposure to that antigenSelf tolerance – prevents the body to elicit an immune

attack against its own tissuesMechanisms 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 developmentTolerance is NOT genetically programmedThe 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 epitopesThe number of lymphocytes able to respondMicroenvironment 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.

Auto immune Disease

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 Immunity

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 ANTIGENSS.No Antigen Name Normal value/ location Associated disease

1 Alpha Fetoprotein (AFP) An AFP level of less than 10 ng/mLFoetal 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/mlSmoker : 0-5ng/mlNormally 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 ANTIGENS.No Antigen Name Normal value/ location Associated disease

1 Cancer antigen 125 Normal value <35U/mlNormally 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/mlPatient 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/mlNormally 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/mlNormally 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 MARKERSS.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