Autoimmunity

Prof M.I.N. Matee

Department of Microbiology and Immunology

School of Medicine

MUCHS

Autoimmunity

Immunologic tolerance Body develops a tolerance for own tissue

and does not produce a rejection response

Autoimmunity Tolerance to own tissues is lost and host

produces an immunologic rejection of own tissue

AUTOIMMMUNITY & AUTOIMMUNE DISEASES

Any body protein and many carbohydrates and lipids, as well as nucleic acids are potential antigens.

The body is capable of constructing T-Cell receptors (TCRs) or B-Cell receptors (BCRs) that can recognise these antigens and initiate an immune response against them.

Mechanisms & Causes of Autoimmunity

The occurrence of autoimmune diseases indicates the presence in the body of autoreactive lymphocyte clones which can, under certain circumstances, become activated.

a) Some self molecules are expressed at levels below the sensitivity threshold of lymphocytes.

b) Some molecules are protected by a barrier from contact with lymphocytes.

c) Some epitopes are normally hidden from the immune system and tolerance towards them is not established.

d) Autoreactive clones made tolerant by anergization can be reactivated under some circumstances.

e) Some autoreactive clones may be kept in check by regulatory mechanisms involving, for example, the suppressor T cells, and when these mechanisms fail the clones may become active.

Autoimmunity - Possible mechanisms

Sequestered antigens antigens lack access to antibody forming cells

Modified cross-reacting antigens fragmentation and recombination of antigens

Forbidden clone/clonal anergy lymphocytes developed in fetus against an

autoantigen and not eliminated Immunological deficiency

anti-idiotype and T-cell suppression not functioning

Molecular Mimicry

The main assumption of the molecular mimicry hypothesis is that some epitopes on foreign antigens are sufficiently similar to certain self epitopes to become target of immune response elicited by the former.

Uncovering of Sequestered Antigens or Cryptic epitopes

An injury or infection may temporarily release molecules normally inaccessible to the immune mechanism, which can then stimulate autoimmune attack on the cell carrying them.

Activation of Potentially Autoreactive T-Cell clones by superantigens:

Autoimmune reaction can also be triggered by superantigens, produced by some microorganisms.

Genetic Factors

Familial associations and susceptibility of inbred mouse strains to certain autoimmune diseases indicate that the development of autoimmunity depends on genetic factors.

Failure of Immune Regulation

Some autoimmune diseases are caused by an impairment of negative regulatory T cells (T-suppressor cells) that normally inhibit potentially autoreactive clones.

Causes of Tissue Damage

Autoimmunity develops into a disease when components of the immune system begin to damage the body. The mechanisms of tissue damage vary according to the types of autoimmune disease.

Examples of Autoimmune Diseases

Diseases Caused Mainly by Autoantibodies.

SLE: Systemic Lupus Erythematosus, Autoantibodies produced against DNA and other nuclear components.

Grave’s disease (Hyperthyroidism)

Autoantibodies produced against the thyroid-stimulating hormone (TSH) receptor that mimic the action of TSH and stimulate excessive production of thyroid hormones (T4, T3).

Hashimoto’s disease (Hypothyroidism)

Autoantibodies produced against thyroid antigens such as thyroglobulin.

Pernicious Anemia

Caused by autoantibodies against intrinsic factor, a membrane protein of intestinal epithelial cells, which is involved in transport of Vitamin B12.

Atrophy of the mucosal cells of the stomach and infiltration of lymphoid tissue

Diseases caused by autoreactive T cells

Insulin-dependent diabetes mellitus.

In IDDN, insulin-producing cells of the pancreatic islets of Langerhans are destroyed by CD8+ Tc cells.

Rheumatoid Arthritis.

The disease is probably caused by TH1 CD4+ cells reacting with fragments of joints antigens such as collagen or a heat shock protein bound to MHC class II molecules.

Autoimmune Diseases - Hematological

Autoimmune Hemolytic Anemia Two types

Warm Cold

May be secondary to another immune disease or idiopathic

Autoimmune DiseasesHematological

Warm Autoimmune Hemolytic Anemia Sometimes minimal but may be life

threatening RBC are sensitized with IgG, C’ or both Selective immunodeficiency seems to

predispose to the disease - may have other autoimmune conditions - may be associated with other abnormal hematological disorders

Transfusion problems

Autoimmune DiseasesHematological

Cold Autoimmune Hemolytic Anemia Acute and transient or chronic forms Acute often follows an infection from

Mycoplasma, viruses, hepatitis, syphillis Chronic form found in older people and the

anemia is worse in the winter. Testing - cold agglutinin test

dilute patient’s serum and react with patient’s cells

Autoimmune DiseasesHematological

Paroxysmal Nocturnal Hemoglobinuria C’3 activation and destruction of cells Activation occurs in acidic environment

Addison’s Disease

Lymphocytic infiltration of the adrenal gland and antibodies to adrenal cells

Often associated with thyroid disease, pernicious anemia and diabetes

Tests - Complement fixation and immunoflourescent immunologic demonstration of antibodies

Autoimmune DiseasesEndocrine System

Thyroid diseases Hashimoto Thyroiditis

lymphoid invasion of thyroid gland and resulting hypothyroidism

Antibodies against cellular thyroid elements and thyroglobulins

Grave’s Disease Antibody that mimics TSH causes hyperplasia of

the thyroid also causes exopthalmus Tests

Detection of thyroid antibodies

Autoimmune DiseasesGastrointestinal Tract

Ulcerative Colitis Inflammatory disease of the colon and

rectum/ allergy or cell mediated often associated with other autoimmune

diseases Some have antibodies against sterile

fetal colon tissue detected with immunoflourescence

Autoimmune DiseasesNeuromuscular

Myasthenia Gravis Acetylcholine is prevented from

stimulating muscle to contract Antibodies to acetylcholine receptors and

thymus abnormalities

Autoimmune DiseasesNeuromuscular

Multiple sclerosis demyelination of the white matter of the

central nervous system presence of lymphocytes in the early

lesions and plasma cells, lymphocytes and macrophages in later lesions

Testing for increased IgG levels in CSF

Autoimmune DiseasesLiver

Primary Biliary Cirrhosis affects the small intrahepatic bile ducts and

eventually leads to liver failure presence of high titer anti-mitochondrial

antibody Chronic Active Hepatitis

Infiltration of lymphocytes and plasma cells Diminished number and function of suppressor

T cells and presence of autoantibodies to different organs

Autoimmune Diseases

Goodpasture’s Syndrome Glomerularnephritis and pulmonary

damage Antibodies against basement membrane

Bullous Skin Disease Antibodies against intercellular bridges of

the cells in the epidermis

GROUP A BETA HEMOLYTICSTREP SEQUELAE

Glomerulonephritis often follows infection with Group A types

12, 4, or 49 and occurs approximately 10 days after throat infection and 20 days after skin infections

Cause may be due ag-ab immune complex at the glomerular membrane which activates complement and causes destruction

GROUP A BETA HEMOLYTICSTREP SEQUELAE

Rheumatic Fever Follows multiple infections with different

types of Group A Beta Hemolytic Strep Includes inflammation and injury to the

joints, heart and central nervous system. Possibility of a cross reacting antibody or

modified antigen which results in damage